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Angiotensin converting enzyme-2 confers endothelial protection and attenuates atherosclerosis

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Abstract

The endothelium plays a central role in the maintenance of vascular homeostasis. One of the main effectors of endothelial dysfunction is ANG II, and pharmacological approaches to limit ANG II bioactivity remain the cornerstone of cardiovascular therapeutics. Angiotensin converting enzyme-2 (ACE2) has been identified as a critical negative modulator of ANG II bioactivity, counterbalancing the effects of ACE in determining net tissue ANG II levels; however, the role of ACE2 in the vasculature remains unknown. In the present study, we hypothesized that ACE2 is a novel target to limit endothelial dysfunction and atherosclerosis. To this aim, we performed in vitro gain and loss of function experiments in endothelial cells and evaluated in vivo angiogenesis and atherosclerosis in apolipoprotein E-knockout mice treated with AdACE2. ACE2-deficient mice exhibited impaired endothelium-dependent relaxation. Overexpression of ACE2 in human endothelial cells stimulated endothelial cell migration and tube formation, and limited monocyte and cellular adhesion molecule expression; effects that were reversed in ACE2 gene silenced and endothelial cells isolated from ACE2-deficient animals. ACE2 attenuated ANG II-induced reactive oxygen species production in part through decreasing the expression of p22phox. The effects of ACE2 on endothelial activation were attenuated by pharmacological blockade of ANG-(1-7) with A779. ACE2 promoted capillary formation and neovessel maturation in vivo and reduced atherosclerosis in apolipoprotein E-knockout mice These data indicate that ACE2, in an ANG-(1-7)-dependent fashion, functions to improve endothelial homeostasis via a mechanism that may involve attenuation of NADPHox-induced reactive oxygen species production. ACE2-based treatment approaches may be a novel approach to limit aberrant vascular responses and atherothrombosis.

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... The ACE/Ang II/AGTR1 and ACE2/Ang-(1-7)/AT2R/MasR pathways are co-expressed in most tissues and act in both autocrine and paracrine manners. ACE2 is relatively abundantly expressed in the heart, mainly in pericytes and cardiomyocytes, and at much lower levels in ECs and fibroblasts, [93,[122][123][124][125][126][127][128][129][130][131][132][133][134][135][136] although some studies have reported that ACE2 is not expressed in human cardiac ECs. [137] SARS-CoV-2 infection downregulates ACE2, leading to disrupted Ang II metabolism [138] and vascular permeability, [139] increased Ang II availability and Ang-(1-7) deficiency, increased inflammation, endothelial activation, leukocyte recruitment, and even platelet activation [ Figure 2]. ...
... Ace2 gene transfer attenuates atherosclerosis in mice by reducing angiogenesis and regulating monocyte-EC interaction via decreasing the expression of adhesion molecules in ECs through Ang-(1-7) production. [134,135] Blood pressure is also increased in ACE2-deficient mice. [145] Lentiviral-mediated overexpression of ACE2 improved blood pressure and hypertensionassociated pathologies. ...
... [203] ECs express ACE2. [129][130][131][132][133][134][135]203] IL-6 and hepcidin enhance ACE2 expression in human pulmonary artery ECs [131] and these 2 molecules are strongly correlated with SARS-CoV-2 infection severity. [204][205][206] Virus infection causes EC death and consequent inflammatory cell infiltration and microvascular pro-thrombotic events. ...
Article
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COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection likely ranks among the deadliest diseases in human history. As with other coronaviruses, SARS-CoV-2 infection damages not only the lungs but also the heart and many other organs that express angiotensin-converting enzyme 2 (ACE2), a receptor for SARS-CoV-2. COVID-19 has upended lives worldwide. Dietary behaviors have been altered such that they favor metabolic and cardiovascular complications, while patients have avoided hospital visits because of limited resources and the fear of infection, thereby increasing out-hospital mortality due to delayed diagnosis and treatment. Clinical observations show that sex, age, and race all influence the risk for SARS-CoV-2 infection, as do hypertension, obesity, and pre-existing cardiovascular conditions. Many hospitalized COVID-19 patients suffer cardiac injury, acute coronary syndromes, or cardiac arrhythmia. SARS-CoV-2 infection may lead to cardiomyocyte apoptosis and necrosis, endothelial cell damage and dysfunction, oxidative stress and reactive oxygen species production, vasoconstriction, fibrotic and thrombotic protein expression, vascular permeability and microvascular dysfunction, heart inflammatory cell accumulation and activation, and a cytokine storm. Current data indicate that COVID-19 patients with cardiovascular diseases should not discontinue many existing cardiovascular therapies such as ACE inhibitors, angiotensin receptor blockers, steroids, aspirin, statins, and PCSK9 inhibitors. This review aims to furnish a framework relating to COVID-19 and cardiovascular pathophysiology.
... RAS major components are renin, angiotensin, AGT, ACE and AT1R [31]. A homologue of ACE, named ACE2, with opposite effect, has been identified and considered to be a key player in the RAS [32,33]. ACE2 protein, a transmembrane metallo-carboxypeptidase of type I, is mainly found on the renal epithelium, endothelial cells of vasculature and Leydig cells of testes [34]. ...
... The balance of ACE and ACE2 regulates the physiological homeostasis of this system. In fact, RAS supports a series of complex enzymatic reaction in which ACE transforms Ang I to a vasoactive vital peptide Ang II [32,33,36]. Two types of receptor for Ang II have been identified: AT1R and AT2R [37,38]. ...
... However, ACE2 counterbalances Ang II-AT1R effects by either stimulating an alternative pathway for Ang I degradation to produce Ang-(1-9), or by inactivating Ang II and hydrolyzing it to a heptapeptide Ang-(1-7). The latter stimulates vasodilation and activates anti-inflammatory, anti-fibrotic and anti-thrombotic cascades via the MasR axis [32,36], as well as the protection of endothelial cell activity [30]. Indeed, it has been shown that in failing hearts, ACE2 level was upregulated, and that ACE2-lacking mice showed damage to heart contractility and renal diseases, implicating an essential role of ACE2 in the regulation of Ang II biological activity [32]. ...
Article
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The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has first been identified in Eastern Asia (Wuhan, China) in December 2019. The virus has then spread to Europe and across all continents where it has led to higher mortality and morbidity, and was declared as a pandemic by the World Health Organization (WHO) in March 2020. Recently, different vaccines have been produced and seem to be more or less effective in protecting from COVID-19. The renin-angiotensin system (RAS), an essential enzymatic cascade involved in maintaining blood pressure and electrolyte balance, is involved in the pathogenicity of COVID-19 since the angiotensin-converting enzyme II (ACE2) acts as the cellular receptor for SARS-CoV-2 in many human tissues and organs. In fact, the viral entrance promotes a downregulation of ACE2 followed by RAS balance dysregulation and an overactivation of the angiotensin II (Ang II)-angiotensin II type I receptor (AT1R) axis which is characterized by a strong vasoconstriction and the induction of the profibrotic, proapoptotic and proinflammatory signalizations in lungs and other organs. This mechanism is featured by a massive cytokine storm, hypercoagulation, an acute respiratory distress syndrome (ARDS), and a subsequent multiple organ damage. While all individuals are vulnerable to the SARS-CoV-2, the disease outcome and severity differ among people and countries and depends on a dual interaction between the virus and the host affected. Many studies have already pointed out the importance of host genetic polymorphisms (especially in the RAS) as well as other related factors such age, gender, lifestyle and habits, and underlying pathologies or comorbidities (diabetes and cardiovascular diseases) that could render individuals at higher risk of infection and pathogenicity. In this review, we explore the correlation between all these risk factors as well as how and why could they account for the severe post-COVID-19 complications.
... Additionally, Mas-receptor deficiency augmented AngII-induced atherosclerosis and plaque rupture through mechanisms involving increased oxidative stress, inflammation, and apoptosis [184]. All of these complications were abolished by overexpression of ACE2 [54,[186][187][188][189] and treatment with ACE2 activator (DIZE) [190,191] or subcutaneous Ang(1-7) [192]. Taken together, there is evidence regarding components of ACE2-Ang(1-7)-Mas axis involvement in CAD devolvement and progression; however, to further elucidate the therapeutic potential of modulation of this axis will require utilization of more selective tools to separate the upstream RAS effects provided by ACE inhibitors or AT1 blockers in general CAD therapy. ...
... Heart failure (early stage) rhACE2 A779 mouse [163] Heart failure (late stage) ACE2-Tg rat [161,162] Atherosclerosis ACE2-Tg HUVECs [54] ACE2-KO, Mas-KO mouse [184] ACE2 siRNA rat [185] ACE2-Tg A779 mouse [186] ACE2-Tg A779 rabbit [187] ACE2-Tg A779 THP-1 cells [188] ACE2-Tg VSMCs [189] DIZE mouse [190,191] Ang(1-7) A779 mouse [192] Chronic obstructive pulmonary disease/Pulmonary fibrosis ACE2-Tg rat [207] Ang(1-7) mouse [208] ACE2 mouse [226] Pulmonary hypertension rhACE2 human [206] Ang(1-7)-Tg PMVECs [229] ACE2-Tg PASMCs [230] rACE2 pig [231] ACE2-Tg A779 rat [251] ACE2-KO ACE2-Tg mouse [258] ACE2-Tg mouse [259] Resorcinolnaphthalein A779 rat [260] XNT rat [261] Resorcinolnaphthalein MLN4760 rat [262] A779 rat [263] NCP-2454 rat [264] Ang(1-7) rat [25,265] rhACE2 human [267] * ongoing clinical trials. ...
Article
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Alternative branches of the classical renin–angiotensin–aldosterone system (RAS) represent an important cascade in which angiotensin 2 (AngII) undergoes cleavage via the action of the angiotensin-converting enzyme 2 (ACE2) with subsequent production of Ang(1-7) and other related metabolites eliciting its effects via Mas receptor activation. Generally, this branch of the RAS system is described as its non-canonical alternative arm with counterbalancing actions to the classical RAS, conveying vasodilation, anti-inflammatory, anti-remodeling and anti-proliferative effects. The implication of this branch was proposed for many different diseases, ranging from acute cardiovascular conditions, through chronic respiratory diseases to cancer, nonetheless, hypoxia is one of the most prominent common factors discussed in conjugation with the changes in the activity of alternative RAS branches. The aim of this review is to bring complex insights into the mechanisms behind the various forms of hypoxic insults on the activity of alternative RAS branches based on the different duration of stimuli and causes (acute vs. intermittent vs. chronic), localization and tissue (heart vs. vessels vs. lungs) and clinical relevance of studied phenomenon (experimental vs. clinical condition). Moreover, we provide novel insights into the future strategies utilizing the alternative RAS as a diagnostic tool as well as a promising pharmacological target in serious hypoxia-associated cardiovascular and cardiopulmonary diseases.
... The literature is however conflicting as to whether endothelial cells (ECs) are directly infected by SARS-CoV-2 or not. Endothelial ACE2 expression has been reported based on immunodetection (Hamming et al., 2004;Lovren et al., 2008;Sluimer et al., 2008) or single-cell RNA sequencing (scRNA-seq) studies (Muus et al., 2021), and the presence of SARS-CoV-2 virus particles in ECs in COVID-19 patients has been proposed (Ackermann et al., 2020;Varga et al., 2020), although the data interpretation has also been questioned (Goldsmith et al., 2020). In contrast to these observations, we failed to both detect endothelial ACE2 expression in human transcriptomic data and infect human ECs in vitro (McCracken et al., 2021). ...
... At the mRNA level, intestinal enterocytes showed high levels of Ace2 expression ( Figure S7). (Ackermann et al., 2020;Lovren et al., 2008;Muus et al., 2021;Varga et al., 2020), whereas other studies advocate pericytes as a major site of ACE2expression He et al., 2016He et al., , 2018Nicin et al., 2020;Vanlandewijck et al., 2018). In line with the latter notion, a recent study (McCracken et al., 2021) reported that the low-level ACE2 mRNA expression observed in human ECs (Muus et al., 2021) is likely caused by pericyte contamination. ...
Article
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Humanized mouse models and mouse-adapted SARS-CoV-2 virus are increasingly used to study COVID-19 pathogenesis, so it is important to learn where the SARS-CoV-2 receptor ACE2 is expressed. Here we mapped ACE2 expression during mouse postnatal development and in adulthood. Pericytes in the CNS, heart, and pancreas express ACE2 strongly, as do perineurial and adrenal fibroblasts, whereas endothelial cells do not at any location analyzed. In a number of other organs, pericytes do not express ACE2, including in the lung where ACE2 instead is expressed in bronchial epithelium and alveolar type II cells. The onset of ACE2 expression is organ specific: in bronchial epithelium already at birth, in brain pericytes before, and in heart pericytes after postnatal day 10.5. Establishing the vascular localization of ACE2 expression is central to correctly interpret data from modeling COVID-19 in the mouse and may shed light on the cause of vascular COVID-19 complications.
... In this study, the immunolocalization of ACE2 protein in macrophages and SMC actin-positive cells from rabbit atherosclerotic plaques was shown. After that, an anti-atherogenic role of ACE2 was confirmed in several experiments and observations [48,49]. ...
... Moreover, ACE2 upregulated PI3K-Akt pathway and downregulated Ang-ll/ROS/NF-κB signaling pathway, as well as JAK-STAT, ERK1/2, and p38 MAPK pathways [50]. Similarly, in ApoE-KO mice, ACE2 overexpression appeared to aggravate the size of atherosclerotic lesions, improve endothelial homeostasis, at least in part, via a mechanism involving an inhibition of Ang-II-induced production of reactive oxygen species [49]. Zhang et al. [51] identified the prevention of atherosclerotic plaque evolution due to the inflammatory response suppression. ...
Article
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COVID-19 is a highly contagious new infection caused by the single-stranded RNA Sars-CoV-2 virus. For the first time, this infection was recorded in December 2019 in the Chinese province of Wuhan. The virus presumably crossed the interspecies barrier and passed to humans from a bat. Initially, the disease was considered exclusively in the context of damage to the respiratory system, but it quickly became clear that the disease also entails serious consequences from various systems, including the cardiovascular system. Among these consequences are myocarditis, myocardial damage, subsequent heart failure, myocardial infarction, and Takotsubo syndrome. On the other hand, clinical data indicate that the presence of chronic diseases in a patient aggravates the course and outcome of coronavirus infection. In this context, the relationship between COVID-19 and atherosclerosis, a condition preceding cardiovascular disease and other disorders of the heart and blood vessels, is particularly interesting. The renin-angiotensin system is essential for the pathogenesis of both coronavirus disease and atherosclerosis. In particular, it has been shown that ACE2, an angiotensin-converting enzyme 2, plays a key role in Sars-CoV-2 infection due to its receptor activity. It is noteworthy that this enzyme is important for the normal functioning of the cardiovascular system. Disruptions in its production and functioning can lead to various disorders, including atherosclerosis.
... It occurs through the binding of spike (S) protein on virus surface to a host cell transmembrane receptor complex that facilitates its cleavage and the subsequent fusion of viral and cellular membranes, thus allowing viral RNA entry into host cells [6,7]. Recently, angiotensin-converting enzyme-2 (ACE2), an enzyme that plays a critical role in the renin-angiotensin system (RAS), has been identified as the main receptor for SARS-CoV-2 S protein [7,8]. Moreover, the transmembrane serine protease-2 (TMPRSS2) and cathepsin-B/L (CTSB/L) has been identified as the main proteases involved in S protein cleavage and processing by host cells [6,7,8]. ...
... Recently, angiotensin-converting enzyme-2 (ACE2), an enzyme that plays a critical role in the renin-angiotensin system (RAS), has been identified as the main receptor for SARS-CoV-2 S protein [7,8]. Moreover, the transmembrane serine protease-2 (TMPRSS2) and cathepsin-B/L (CTSB/L) has been identified as the main proteases involved in S protein cleavage and processing by host cells [6,7,8]. ACE2 high expression levels in respiratory epithelial cells accounts for the initial respiratory symptoms in COVID-19 [6,7]. ...
Preprint
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COVID-19 is a respiratory disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). COVID-19 pathogenesis causes vascular-mediated neurological disorders via still elusive mechanisms. SARS-CoV-2 infects host cells by binding to angiotensin-converting enzyme 2 (ACE2), a transmembrane receptor that recognizes the viral spike (S) protein. Brain pericytes were recently shown to express ACE2 at the neurovascular interface, outlining their possible implication in microvasculature injury in COVID-19. Yet, pericyte responses to SARS-CoV-2 is still to be fully elucidated. Using cell-based assays, we report that ACE2 expression in human brain vascular pericytes is highly dynamic and is increased upon S protein stimulation. Pericytes exposed to S protein underwent profound phenotypic changes translated by increased expression of contractile and myofibrogenic proteins, namely α-smooth muscle actin (α-SMA), fibronectin, collagen I, and neurogenic locus notch homolog protein-3 (NOTCH3). These changes were associated to an altered intracellular calcium (Ca2+) dynamic. Furthermore, S protein induced lipid peroxidation, oxidative and nitrosative stress in pericytes as well as triggered an immune reaction translated by activation of nuclear factor-kappa-B (NF-κB) signalling pathway, which was potentiated by hypoxia, a condition associated to vascular comorbidities, which exacerbate COVID-19 pathogenesis. S protein exposure combined to hypoxia enhanced the production of pro-inflammatory cytokines involved in immune cell activation and trafficking, namely interleukin-8 (IL-8), IL-18, macrophage migration inhibitory factor (MIF), and stromal cell-derived factor-1 (SDF-1). Finally, we found that S protein could reach the mouse brain via the intranasal route and that reactive ACE2-expressing pericytes are recruited to the damaged tissue undergoing fibrotic scarring in a mouse model of cerebral multifocal micro-occlusions, a main reported vascular-mediated neurological condition associated to COVID-19. Our data demonstrate that the released S protein is sufficient to mediate pericyte immunoreactivity, which may contribute to microvasculature injury in absence of a productive viral infection. Our study provides a better understanding for the possible mechanisms underlying cerebrovascular disorders in COVID-19, paving the way to develop new therapeutic interventions.
... It occurs through the direct binding of viral Spike (S) protein to a host cell transmembrane receptor complex that facilitates its cleavage and the subsequent fusion of viral and cellular membranes, thus allowing viral RNA entry into host cells (Hoffmann et al., 2020;Ou et al., 2020). Recently, angiotensin-converting enzyme-2 (ACE2), an enzyme that plays a critical role in the renin-angiotensin system (RAS), has been identified as the main receptor for SARS-CoV-2 S protein (Ou et al., 2020;Lovren et al., 2008). Moreover, the transmembrane serine protease-2 (TMPRSS2) and cathepsin-B/L (CTSB/L) has been identified as the main proteases involved in S protein cleavage and processing by host cells (Hoffmann et al., 2020;Ou et al., 2020;Lovren et al., 2008). ...
... Recently, angiotensin-converting enzyme-2 (ACE2), an enzyme that plays a critical role in the renin-angiotensin system (RAS), has been identified as the main receptor for SARS-CoV-2 S protein (Ou et al., 2020;Lovren et al., 2008). Moreover, the transmembrane serine protease-2 (TMPRSS2) and cathepsin-B/L (CTSB/L) has been identified as the main proteases involved in S protein cleavage and processing by host cells (Hoffmann et al., 2020;Ou et al., 2020;Lovren et al., 2008). ACE2 high expression levels in respiratory epithelial cells accounts for the initial respiratory symptoms observed in COVID-19 (Hoffmann et al., 2020;Ou et al., 2020). ...
Article
Full-text available
Coronavirus disease 19 (COVID-19) is a respiratory disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). COVID-19 pathogenesis causes vascular-mediated neurological disorders via elusive mechanisms. SARS-CoV-2 infects host cells via the binding of viral Spike (S) protein to transmembrane receptor, angiotensin-converting enzyme 2 (ACE2). Although brain pericytes were recently shown to abundantly express ACE2 at the neurovascular interface, their response to SARS-CoV-2 S protein is still to be elucidated. Using cell-based assays, we report that ACE2 expression in human brain vascular pericytes was increased upon S protein exposure. Pericytes exposed to S protein underwent profound phenotypic changes associated with an elongated and contracted morphology accompanied with an enhanced expression of contractile and myofibrogenic proteins, such as α-smooth muscle actin (α-SMA), fibronectin, collagen I, and neurogenic locus notch homolog protein-3 (NOTCH3). On the functional level, S protein exposure also promoted the acquisition of Ca²⁺ signature of contractile ensheathing pericytes characterized by highly regular oscillatory Ca²⁺ fluctuations. Furthermore, S protein induced lipid peroxidation, oxidative and nitrosative stress in pericytes as well as triggered an immune reaction translated by activation of nuclear factor-kappa-B (NF-κB) signaling pathway, which was potentiated by hypoxia, a condition associated with vascular comorbidities that exacerbate COVID-19 pathogenesis. S protein exposure combined to hypoxia enhanced the production of pro-inflammatory cytokines involved in immune cell activation and trafficking, namely macrophage migration inhibitory factor (MIF). Using transgenic mice expressing the human ACE2 that recognizes S protein, we observed that the intranasal infection with SARS-CoV-2 rapidly induced hypoxic/ischemic-like pericyte reactivity in the brain of transgenic mice, accompanied with an increased vascular expression of ACE2. Moreover, we found that SARS-CoV-2 S protein presents in the intranasal cavity reached the brain of mice in which the nasal mucosa was deregulated. Collectively, these findings suggest that SARS-CoV-2 S protein impairs the vascular and immune regulatory functions of brain pericytes, which may account for vascular-mediated brain damage. Our study provides a better understanding for the mechanisms underlying cerebrovascular disorders in COVID-19, paving the way to develop new therapeutic interventions.
... Coronaviruses (CoVs) are enveloped viruses with positive-sense 5 -3 singlestranded RNA of the Coronaviridae family [1]. These viruses are around 125 nm particles and contain a viral genome of around 30 (26)(27)(28)(29)(30)(31)(32) kb pairs. The virions have a structural spike glycoprotein, an M-membrane protein (a type III transmembrane glycoprotein), an Nnucleocapsid protein (which is present within the phospholipid bilayer), and non-structural proteins [1]. ...
... We characterized HUVEC for the expression of the typical endothelial markers (Supplementary Figure S1), confirming the presence of CD31, CD105, Cells 2022, 11, 146 9 of 16 CD146, CD54, VEGFR-2 endothelial markers and not of CD45 [26][27][28][29]. Moreover, we confirmed the ACE2 (spike receptor) expression by HUVEC, as demonstrated by previous studies [30][31][32] using cytofluorimetric analysis (Supplementary Figure S1). Therefore, we analyzed the possible interaction of S-EVs with target cells. ...
Article
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Extracellular vesicles (EVs) and viruses share common features: size, structure, biogenesis and uptake. In order to generate EVs expressing the SARS-CoV-2 spike protein on their surface (S-EVs), we collected EVs from SARS-CoV-2 spike expressing human embryonic kidney (HEK-293T) cells by stable transfection with a vector coding for the S1 and S2 subunits. S-EVs were characterized using nanoparticle tracking analysis, ExoView and super-resolution microscopy. We obtained a population of EVs of 50 to 200 nm in size. Spike expressing EVs represented around 40% of the total EV population and co-expressed spike protein with tetraspanins on the surfaces of EVs. We subsequently used ACE2-positive endothelial and bronchial epithelial cells for assessing the internalization of labeled S-EVs using a cytofluorimetric analysis. Internalization of S-EVs was higher than that of control EVs from non-transfected cells. Moreover, S-EV uptake was significantly decreased by anti-ACE2 antibody pre-treatment. Furthermore, colchicine, a drug currently used in clinical trials, significantly reduced S-EV entry into the cells. S-EVs represent a simple, safe, and scalable model to study host-virus interactions and the mechanisms of novel therapeutic drugs.
... Thus, it is currently believed that the evolution of respiratory cases to death due to cardiovascular shock caused by thromboembolism is associated with the connection between COVID-19 and endothelial ACE2 expression, however it is still not completely elucidated, but probably occurs microvascular compromise [24,25]. The prognosis may be even more unfavorable, because in some patients, this virus can also affect the central nervous system (CNS) [24,26]. ...
... The preclinical study of T. cruzi infection, since 1909, demonstrated a diverse use of biomodels, such as mice, rats, dogs and opossums [25]. However, with the refinement of techniques and the use of transgenic models using the mouse model, it became possible, especially in Outbred Stock mice, to evaluate, in a short period of time, the evolution of the acute phase, the symptoms in the chronic phase and the effectiveness of experimental compounds, more closely the possibility of translating the results to the patient with reliability [17]. ...
Article
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Dr. Carlos Chagas, in 1909, published his notable discovery, a new pathology denominated Chagas disease. He was able to identify: etiologic agent, the protozoan Trypanosoma cruzi, its biological cycle and your pathogenesis: etiologic agent, the protozoan T. cruzi its biological cycle and your pathogenesis. However, to date, there is still no vaccine or effective treatment for the symptomatic chronic phase. In 2019, a new Severe Acute Respiratory Syndrome, promoted by a member of the Coronavirus family, emerged in Wuhan (China province), whose origin has not yet been totally elucidate. SARS-Cov-2 or COVID-19 is characterize by high transmissibility and high morbidity. Thus, in 2020 it became a global pandemic. Highlights into similarities between a neglected disease, which affects 40.000 new cases per year and intense research for a vaccine and treatment using experimental models and severe COVID-19 infection, with millions of victims, by evolution to cardiovascular disturbance, mainly through its target point to ACE2 enzyme. To compare acute T. cruzi experimental infection in mice, the cardiorenal axis involvement and suggest possible common points to research about serious course of the COVID- 19 infection and cardiovascular involvement
... ACE2 mRNA and protein levels, as well as enzymatic activity, were shown to be upregulated in explanted hearts from patients with end-stage HF, as well as in the HF rat model [179][180][181]. Myocytes, fibroblasts, vascular smooth muscle cells, pericytes [182] and endothelial cells of the coronaries [183] express ACE2, while myocytes in patients suffering from heart disease exhibit higher ACE2 expression [184]. Pericytesthe mural cells lining microvasculature, interacting with endothelial cells notably to maintain microvascular stability-exhibited the strongest ACE2 expression in HF patients [185], rendering these cells involved in the coronary vasculature of the myocardium, more susceptible to infection. ...
Article
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Addressing factors modulating COVID-19 is crucial since abundant clinical evidence shows that outcomes are markedly heterogeneous between patients. This requires identifying the factors and understanding how they mechanistically influence COVID-19. Here, we describe how eleven selected factors (age, sex, genetic factors, lipid disorders, heart failure, gut dysbiosis, diet, vitamin D deficiency, air pollution and exposure to chemicals) influence COVID-19 by applying the Adverse Outcome Pathway (AOP), which is well-established in regulatory toxicology. This framework aims to model the sequence of events leading to an adverse health outcome. Several linear AOPs depicting pathways from the binding of the virus to ACE2 up to clinical outcomes observed in COVID-19 have been developed and integrated into a network offering a unique overview of the mechanisms underlying the disease. As SARS-CoV-2 infectibility and ACE2 activity are the major starting points and inflammatory response is central in the development of COVID-19, we evaluated how those eleven intrinsic and extrinsic factors modulate those processes impacting clinical outcomes. Applying this AOP-aligned approach enables the identification of current knowledge gaps orientating for further research and allows to propose biomarkers to identify of high-risk patients. This approach also facilitates expertise synergy from different disciplines to address public health issues.
... As a proof of concept of the possible implication of sHLA-G levels in the COVID-19 course, we evaluated the levels of biomarkers of endothelial activation and correlated them with sHLA-G levels. Indeed, the endothelial compartment is a relevant target of SARS-COV2 infection which expresses ACE2 [39,40]. Endothelial dysfunction may play a major contribution to COVID-19 pathophysiology, leading to loss of physiological properties of the endothelium, including the ability to stimulate vasodilation, fibrinolysis, and antiaggregation [41]. ...
Article
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Human leukocyte antigen (HLA) is a group of molecules involved in inflammatory and infective responses. We evaluated blood sHLA-E and sHLA-G levels in hospitalized COVID-19 patients with respiratory failure and their relationship with clinical evolution, changes in endothelial activation biomarker profile, and neutrophil adhesion. sHLA-E, sHLA-G, and endothelial activation biomarkers were quantified by ELISA assay in plasma samples. Neutrophil adhesion to endothelium was assessed in the presence/absence of patients’ plasma samples. At admission, plasma levels of sHLA-G and sHLA-E were significantly higher in COVID-19 patients with respiratory failure compared to controls. COVID-19 clinical improvement was associated with increased sHLA-G plasma levels. In COVID-19, but not in control patients, an inverse correlation was found between serum sICAM-1 and E-selectin levels and plasma sHLA-G values. The in vitro analysis of activated endothelial cells confirmed the ability of HLA-G molecules to control sICAM-1 and sE-selectin expression via CD160 interaction and FGF2 induction and consequently neutrophil adhesion. We suggest a potential role for sHLA-G in improving COVID-19 patients’ clinical condition related to the control of neutrophil adhesion to activated endothelium.
... Different interwoven and contested articles implicate angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in the enhancement of SARS-CoV-2 infection through overexpression of cardiac ACE2 (Patel and Verma 2020;Sanchis-Gomar et al. 2020). Previously, different studies highlighted the protective role of ACE2 against the development of HF, atherosclerosis, and endothelial dysfunction (Lovren et al. 2008;Wang et al. 2013). Ohtsuki et al. (2010) confirmed that expression of ACE2 improves cardiomyocytes remodeling in patients with end-stage left ventricular HF (Ohtsuki et al. 2010). ...
Article
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Coronavirus disease 2019 (Covid-19) is a novel worldwide pandemic caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). During Covid-19 pandemic, socioeconomic deprivation, social isolation, and reduced physical activities may induce heart failure (HF), destabilization, and cause more complications. HF appears as a potential hazard due to SARS-CoV-2 infection, chiefly in elderly patients with underlying comorbidities. In reality, the expression of cardiac ACE2 is implicated as a target point for SARS-CoV-2-induced acute cardiac injury. In SARS-CoV-2 infection, like other febrile illnesses, high blood viscosity, exaggerated pro-inflammatory response, multisystem inflammatory syndrome, and endothelial dysfunction-induced coagulation disorders may increase risk of HF development. Hypoxic respiratory failure, as in pulmonary edema, severe acute lung injury (ALI), and acute respiratory distress syndrome (ARDS) may affect heart hemodynamic stability due to the development of pulmonary hypertension. Indeed, Covid-19-induced HF could be through the development of cytokine storm, characterized by high proliferation pro-inflammatory cytokines. In cytokine storm-mediated cardiac dysfunction, there is a positive correlation between levels of pro-inflammatory cytokine and myocarditis-induced acute cardiac injury biomarkers. Therefore, Covid-19-induced HF is more complex and related from a molecular background in releasing pro-inflammatory cytokines to the neuro-metabolic derangements that together affect cardiomyocyte functions and development of HF. Anti-heart failure medications, mainly digoxin and carvedilol, have potent anti-SARS-CoV-2 and anti-inflammatory properties that may mitigate Covid-19 severity and development of HF. In conclusion, SARS-CoV-2 infection may lead to the development of HF due to direct acute cardiac injury or through the development of cytokine storms, which depress cardiomyocyte function and cardiac contractility. Anti-heart failure drugs, mainly digoxin and carvedilol, may attenuate severity of HF by reducing the infectivity of SARS-CoV-2 and prevent the development of cytokine storms in severely affected Covid-19 patients.
... The virus uses angiotensin-converting enzyme 2 (ACE2) as an entry receptor, present on the surface of the alveolar type II cells. ACE2 is a transmural metalloprotein (extent from the outer to the inner surface of the cell membrane), consists of zinc and protein base, and is normally involved in the renin/angiotensin pathway by converting angiotensin-2 to angiotensin 1-7 (a peptide with an antioxidant, antiinflammatory and vasodilator properties) [27,28]. ACE2 is the most probable binding site of the SARS-CoV2 particles to the host cell to cause final infection [17,29]. ...
Article
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COVID-19 (Corona Virus Disease-2019) is an infectious disease caused by a novel coronavirus, known as the acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This is a highly contagious disease that has already affected more than 220 countries globally, infecting more than 212 million people and resulting in the death of over 4.4 million people. This review aims to highlight the pertinent documentary evidence upon the adverse effects of the SARS-CoV-2 infection on several vital human organs. SARS-CoV-2 primarily targets the lung tissue by causing diffuse alveolar damage and may result in Acute Respiratory Distress Syndrome (ARDS). SARS-CoV-2 infects the cell via cell surface receptor, angiotensin-converting enzyme 2 (ACE2). Besides lungs, SARS-CoV-2 critically damage tissues in other vital human organs such as the heart, kidney, liver, brain, and gastrointestinal tract. The effect on the heart includes muscle dysfunction (acute or protracted heart failure), myocarditis, and cell necrosis. Within hepatic tissue, it alters serum aminotransferase, total bilirubin, and gamma-glutamyl transferase levels. It contributes to acute kidney injury (AKI). Localized infection of the brain can lead to loss or attenuation of olfaction, muscular pain, headaches, encephalopathy, dizziness, dysgeusia, psychomotor disorders, and stroke; while the gastrointestinal symptoms include the disruption of the normal intestinal mucosa, leading to diarrhoea and abdominal pain. This review encompassed a topical streak of systemic malfunctions caused by the SARS-CoV-2 infection. As the pandemic is still in progress, more studies will enrich our understanding and analysis of this disease.
... There exists a dynamic equilibrium between ACE and ACE2 under the steady-state condition, where the ACE2 acts as a counter regulator of ACE by converting angiotensin II to vasodilatory molecules, Ang 1-7, which is >300 times effective than converting angiotensin I to Ang 1-9. These vasodilatory ang 1-7 molecules [39] aid in protecting the endothelial cell functions by (i) decreasing the protein levels of adhesion molecules, vascular cell adhesion molecules (VCAM) and E-selectin; and (ii) decreasing the production of chemokine and cytokine, monocyte chemoattractant protein-1 (MCP-1) and IL-6 [40] (iii) limiting monocyte recruitment; (iv) attenuating NADPHox induced reactive oxygen species (ROS) generation, partly mediated through the decreased expression of p22phox, a vital component of superoxide-generating vascular NADH/NADPH oxidase [41,42]; (v) increasing eNOS and NO production (eNOS/NO) pathways with a concomitant decrease in NADPH oxidase 2 and oxidase 4 (Nox2 and 4) (Nox/ROS) pathways [43]. The antithrombotic and anti-inflammatory effects exerted by Ang 1-7 is mediated by binding to the Mas receptor [44,45] and by eliciting the production of NO and prostacyclin, an anticoagulant. ...
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The SARS-CoV-2 virus causing COVID-19 disease has emerged expeditiously in the world and has been declared pandemic since March 2020, by World Health Organization (WHO). The destructive effects of SARS-CoV-2 infection are increased among the patients with pre-existing chronic conditions and, in particular, this review focuses on patients with underlying cardiovascular complications. The expression pattern and potential functions of SARS-CoV-2 binding receptors and the attributes of SARS-CoV-2 virus tropism in a physio-pathological state of heart and blood vessel are precisely described. Of note, the atheroprotective role of ACE2 receptors is reviewed. A detailed description of the possible detrimental role of SARS-CoV-2 infection in terms of vascular leakage, including endothelial glycocalyx dysfunction and bradykinin 1 receptor stimulation is concisely stated. Furthermore, the potential molecular mechanisms underlying SARS-CoV-2 induced clot formation in association with host defense components, including activation of FXIIa, complements and platelets, endothelial dysfunction, immune cell responses with cytokine-mediated action are well elaborated. Moreover, a brief clinical update on patient with COVID-19 disease with underlying cardiovascular complications and those who had new onset of cardiovascular complications post-COVID-19 disease was also discussed. Taken together, this review provides an overview of the mechanistic aspects of SARS-CoV-2 induced devastating effects, in vital organs such as the heart and vessels.
... Several studies have suggested a link of ACE-2 to vascular diseases (11,12). Considering this, ACE-2 deficiency consecutively was observed to cause vascular inflammation and atherosclerosis (8,13). In addition, e.g., expression of adhesion molecules (e.g., VCAM), monocyte chemoattractant protein-1 (MCP-1), and interleukin 6 (IL-6) were significantly increased (8,14,15). ...
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), affects the pulmonary systems via angiotensin-converting enzyme-2 (ACE-2) receptor, being an entry to systemic infection. As COVID-19 disease features ACE-2 deficiency, a link to microcirculation is proposed. Optical coherence tomography angiography (OCT-A) enables non-invasive analysis of retinal microvasculature. Thus, an impaired systemic microcirculation might be mapped on retinal capillary system. As recent OCT-A studies, analyzing microcirculation in two subdivided layers, yielded contrary results, an increased subdivision of retinal microvasculature might offer an even more fine analysis. The aim of the study was to investigate retinal microcirculation by OCT-A after COVID-19 infection in three subdivided layers (I). In addition, short-term retinal affections were monitored during COVID-19 disease (II). Considering (I), a prospective study (33 patientspost−COVID and 28 controls) was done. Macula and peripapillary vessel density (VD) were scanned with the Spectralis II. Macula VD was measured in three layers: superficial vascular plexus (SVP), intermediate capillary plexus (ICP), and deep capillary plexus (DCP). Analysis was done by the EA-Tool, including an Anatomical Positioning System and an analysis of peripapillary VD by implementing Bruch's membrane opening (BMO) landmarks. Overall, circular (c1, c2, and c3) and sectorial VD (s1-s12) was analyzed. Considering (II), in a retrospective study, 29 patients with severe complications of COVID-19 infection, hospitalized at the intensive care unit, were monitored for retinal findings at bedside during hospitalization. (I) Overall (p = 0.0133) and circular (c1, p = 0.00257; c2, p = 0.0067; and c3, p = 0.0345). VD of the ICP was significantly reduced between patientspost−COVID and controls, respectively. Overall (p = 0.0179) and circular (c1, p = 0.0189) peripapillary VD was significantly reduced between both groups. Subgroup analysis of hospitalized vs. non-hospitalized patientspost−COVID yielded a significantly reduced VD of adjacent layers (DCP and SVP) with increased severity of COVID-19 disease. Clinical severity parameters showed a negative correlation with VD (ICP) and peripapillary VD. (II) Funduscopy yielded retinal hemorrhages and cotton wool spots in 17% of patients during SARS-CoV-2 infection. As VD of the ICP and peripapillary regions was significantly reduced after COVID-19 disease and showed a link to clinical severity markers, we assume that the severity of capillary impairment after COVID-19 infection is mapped on retinal microcirculation, visualized by non-invasive OCT-A.
... Endothelial cells also express ACE2. In the lung, a major part is occupied by endothelium [12]. COVID 19 mostly affects the elderly people above 50 years initially and the high mortality rate was also noted in elder people. ...
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The global threat acute respiratory tract infection is COVID 19, which emerged in December 2019. There are seven different types of coronavirus which cause illness to humans. Out of 7, SARS-Cov, MERS-Cov, SARS-CoV can affect severely on respiratory systems. Similar protein structure was found in COVID 19 as in acute respiratory distress syndrome (ARDS), so the coronavirus was termed as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Fever, sore throat, cold, dry cough which
... In the RAAS system, angiotensinII (AngII) enhances oxidative stress by stimulating NOX (20). Under normal conditions, ACE2R degrades AngII into Ang1-7, which inhibits NOX and decreases oxidative stress (21). Following the infection of SARS-CoV-2 to ACE2R, ACE2R fails to degrade AngII, consequently accumulating AngII and ROS and causing oxidative stress and cell damage (3). ...
Article
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COVID-19 and lung cancer are two severe pulmonary diseases that cause millions of deaths globally each year. Understanding the dysregulated signaling pathways between them can benefit treating the related patients. Recent studies suggest the critical role of reactive oxygen species (ROS) in both diseases, indicating an interplay between them. Here we reviewed references showing that ROS and ROS-associated signaling pathways, specifically via NRF2, HIF-1, and Nf-κB pathways, may bridge mutual impact between COVID-19 and lung cancer. As expected, typical ROS-associated inflammation pathways (HIF-1 and Nf-κB) are activated in both diseases. The activation of both pathways in immune cells leads to an overloading immune response and exacerbates inflammation in COVID-19. In lung cancer, HIF-1 activation facilitates immune escape, while Nf-κB activation in T cells suppresses tumor growth. However, the altered NRF2 pathway show opposite trends between them, NRF2 pathways exert immunosuppressive effects in both diseases, as it represses the immune response in COVID-19 patients while facilitates the immune escape of tumor cells. Furthermore, we summarized the therapeutic targets (e.g., phytochemicals) on these ROS pathways. In sum, our review focus on the understanding of ROS Signaling in COVID-19 and lung cancer, showing that modulating ROS signaling pathways may alleviate the potentially mutual impacts between COVID-19 and lung cancer patients.
... Both peptides Ang 1-7 and 1-9 have vasodilatory, anti-inflammatory, antioxidant, antifibrotic, and antithrombotic effects in tissues and contribute to reducing blood pressure. 17,39,44,45 Thus, ACE2 has a protective function and could be one of the factors contributing to the lower prevalence of cardiovascular F I G U R E 2 Skeletal muscle ACE2 protein expression and cardiorespiratory fitness. Each straight line represents the linear relationship between the logarithm of the level of ACE2 expression in the human vastus lateralis skeletal muscle and maximal oxygen uptake (VO 2 max, expressed as mL of O 2 per kg of lean mass of the lower extremities (LLM)), for the percentages of body fat indicated. ...
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The study aimed to determine the levels of skeletal muscle Angiotensin‐Converting Enzyme 2 (ACE2, the SARS‐CoV‐2 receptor) protein expression in men and women and assess whether ACE2 expression in skeletal muscle is associated with cardiorespiratory fitness and adiposity. The level of ACE2 in vastus lateralis muscle biopsies collected in previous studies from 170 men (age:19‐65 yrs, weight:56‐137 kg, BMI:23‐44) and 69 women (age:18‐55 yrs, weight:41‐126 kg, BMI:22‐39) was analysed in duplicate by western blot. VO2max was determined by ergospirometry and body composition by DXA. ACE2 protein expression was 1.8‐fold higher in women than men (p=0.001, n=239). This sex difference disappeared after accounting for the percentage of body fat (fat %), VO2max per kg of legs lean mass (VO2max‐LLM) and age (p=0.47). Multiple regression analysis showed that the fat % (β=0.47) is the main predictor of the variability in ACE2 protein expression in skeletal muscle, explaining 5.2 % of the variance. VO2max‐LLM had also predictive value (β=0.09). There was a significant fat % by VO2max‐LLM interaction, such that for subjects with low fat %, VO2max‐LLM was positively associated with ACE2 expression while as fat % increased the slope of the positive association between VO2max‐LLM and ACE2 was reduced. In conclusion, women express higher amounts of ACE2 in their skeletal muscles than men. This sexual dimorphism is mainly explained by sex differences in fat % and cardiorespiratory fitness. The percentage of body fat is the main predictor of the variability in ACE2 protein expression in human skeletal muscle.
... Activation of ACE2 is capable of improving endothelium-dependent relaxation in diabetic and hypertensive animals and the mechanism involves reduction in vascular ROS production [37]. Building into these findings, a previous study demonstrated that in endothelial cells, ACE2 prevents increased ROS generation in response to AngII by regulating p22phox [38]. Moreover, ACE2 knockout vascular smooth muscle cells display higher ROS production and NADPH oxidase activity upon AngII stimulation [39]. ...
Article
Toll-like receptor 4 (TLR4) contributes to the pathophysiology of diabetes. This happens, at least in part, because TLR4 modulates the enzyme NADPH oxidase, a primary source of ROS in vascular structures. Increased oxidative stress disrupts key vascular signaling mechanisms and drives the progression of diabetes, elevating the likelihood of cardiovascular diseases. Recently, it has been shown that patients with diabetes are also at a higher risk of developing severe coronavirus disease 2019 (COVID-19). Given the importance of the interaction between TLR4 and NADPH oxidase to the disrupted diabetic vascular system, we put forward the hypothesis that TLR4-mediated NADPH oxidase-derived ROS might be a critical mechanism to help explain why this disparity appears in diabetic patients, but unfortunately, conclusive experimental evidence still lacks in the literature. Herein, we focus on discussing the pathological implications of this signaling communication in the diabetic vasculature and exploring this crosstalk in the context of diabetes-associated COVID-19.
... Additionally, ACE2 is another important molecule that degrades Ang II to Ang 1-7. This degradation results in the lowering of oxidative stress by inhibiting NADPH oxidase, and also preventing the production of RONS induced by Ang II (Lovren et al., 2008). This information is crucial in understanding the effect of this mechanism on the severity of COVID-19 symptoms. ...
Article
The coronavirus disease (COVID-19) arises from the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) which is an enveloped RNA virus. COVID-19 has rapidly spread throughout the world by infecting more than 143 million people and causing 3.04 million deaths worldwide by 22 April 2021, confirmed by the World Health Organization. It caused great concern and pandemic all over the world, therewithal there has not been found any specific and efficient treatment yet. In the current review, we aimed to define the biophysical and biochemical aspects of SARS-CoV-2, including renin-angiotensin-system, cytokine storms, receptor binding, protein structural and functional features, molecular interactions, and conformational changes that take place during viral attachment and entering into human cells. It was also aimed to highlight the general hallmarks of COVID-19, including treatment strategies, diagnosis and even prevention. Thus, this review will serve as an updated comprehensive body of information and discussion on COVID-19 and will help the molecular scientists, biophysicists, clinicians, as well as medical engineers. Thereby, further understanding of COVID-19 will provide novel insights and advances in development of therapeutic potentials and vaccine alternatives as well as in detection of specific targets for diagnosis.
... 86 In one study, the researchers encouraged the performance of individual atrial ganglionated plexus atlas through high-frequency stimulation (before the ablation procedure) to characterize the loci amenable to targeting during ablation. 87 Epicardial stromal cells were demonstrated to be responsive to catecholaminergic stimulation, which can activate the secretion of proteins from these cells to the neighboring tissue. 49 Adipokines might also affect the cardiac autonomic system and enhance or modulate rapid atrial pacing-induced AF. 88 Late recurrence after catheter ablation (from 3 months to approximately one year after the procedure) in patients affected by paroxysmal AF without HF was independently associated with LA to total EAT volume ratio and greater sympathetic activity. ...
Article
Obesity is a well‐known risk factor for atrial fibrillation (AF). Local epi‐myocardial or intra‐myocardial adiposity caused by aging, obesity, or cardiovascular disease (CVD) is considered to be a better predictor of the risk of AF than general adiposity. Some of the described mechanisms suggest that epicardial adipose tissue (EAT) participates in structural remodeling owing to its endocrine activity or its infiltration between cardiomyocytes. Epicardial fat also wraps up the ganglionated plexi that reach the myocardium. Although the increment of volume/thickness and activity of EAT might modify autonomic activity, autonomic system dysfunction might also change the endocrine activity of epicardial fat in a feedback response. As a result, new preventive therapeutic strategies are focused on reducing adiposity and weight loss before AF ablation or inhibiting autonomic neurotransmitter secretion on fat pads during open‐heart surgery to reduce the recurrence or postoperative risk of AF. In this manuscript, we review some of the novel findings regarding the pathophysiology and associated risk factors of AF, with special emphasis on the role of EAT in the electrical, structural, and molecular mechanisms of AF initiation and maintenance. In addition, we have included a brief note provided on epicardial fat preclinical models that could be useful for identifying new therapeutic targets.
... Another target of SARS-CoV-2 infections is the endothelium, which also expresses ACE2 [10,11], leading to endothelial dysfunction as a major determinant of COVID-19. This may lead to a loss of physiological properties of the endothelium, including the ability to stimulate vasodilation, fibrinolysis, and anti-aggregation [12]. ...
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Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) has been linked to thrombotic complications and endothelial dysfunction. We assessed the prognostic implications of endothelial activation through measurement of endothelin-I precursor peptide (proET-1), the stable precursor protein of Endothelin-1, in a well-defined cohort of patients hospitalized with COVID-19. Methods We measured proET-1 in 74 consecutively admitted adult patients with confirmed COVID-19 and compared its prognostic accuracy to that of patients with community-acquired pneumonia (n = 876) and viral bronchitis (n = 371) from a previous study by means of logistic regression analysis. The primary endpoint was all-cause 30-day mortality. Results Overall, median admission proET-1 levels were lower in COVID-19 patients compared to those with pneumonia and exacerbated bronchitis, respectively (57.0 pmol/l vs. 113.0 pmol/l vs. 96.0 pmol/l, p < 0.01). Although COVID-19 non-survivors had 1.5-fold higher admission proET-1 levels compared to survivors (81.8 pmol/l [IQR: 76 to 118] vs. 53.6 [IQR: 37 to 69]), no significant association of proET-1 levels and mortality was found in a regression model adjusted for age, gender, creatinine level, diastolic blood pressure as well as cancer and coronary artery disease (adjusted OR 0.1, 95% CI 0.0009 to 14.7). In patients with pneumonia (adjusted OR 25.4, 95% CI 5.1 to 127.4) and exacerbated bronchitis (adjusted OR 120.1, 95% CI 1.9 to 7499) we found significant associations of proET-1 and mortality. Conclusions Compared to other types of pulmonary infection, COVID-19 shows only a mild activation of the endothelium as assessed through measurement of proET-1. Therefore, the high mortality associated with COVID-19 may not be attributed to endothelial dysfunction by the surrogate marker proET-1.
... In the respiratory system, its expression is limited (96). ACE2 plays a role in attenuating microvascular pathology and protecting against atherogenesis, endothelial dysfunction, thrombus formation, oxidative stress, and inflammatory cascades responsible for monocyte-endothelial cell interaction (71,97). SARS-CoV-2 interaction with ACE2 could cause astrogliosis and microgliosis, increase BBB permeability, allowing monocyte and leukocyte infiltration to the CNS in multiple brain regions (98,99). ...
Article
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The current pandemic caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a public health emergency. To date, March 1, 2021, coronavirus disease 2019 (COVID-19) has caused about 114 million accumulated cases and 2.53 million deaths worldwide. Previous pieces of evidence suggest that SARS-CoV-2 may affect the central nervous system (CNS) and cause neurological symptoms in COVID-19 patients. It is also known that angiotensin-converting enzyme-2 (ACE2), the primary receptor for SARS-CoV-2 infection, is expressed in different brain areas and cell types. Thus, it is hypothesized that infection by this virus could generate or exacerbate neuropathological alterations. However, the molecular mechanisms that link COVID-19 disease and nerve damage are unclear. In this review, we describe the routes of SARS-CoV-2 invasion into the central nervous system. We also analyze the neuropathologic mechanisms underlying this viral infection, and their potential relationship with the neurological manifestations described in patients with COVID-19, and the appearance or exacerbation of some neurodegenerative diseases.
... Importantly, it has been shown that the membrane isoform of ACE2 serves as a receptor for certain coronaviruses, including SARS-CoV-2 [157], via which this virus enters the cells. The binding of the virus to membrane ACE2 results in the dysfunction of Mas receptor-mediated pathways in the vasculature, reduces downstream NO release, and promotes endothelial dysfunction [157,158]. Moreover, in the endothelium, Ang II acts as one of the endothelium-derived contracting factors (EDCFs) as described below. ...
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Various studies have shown that certain flavonoids, flavonoid-containing plant extracts, and foods can improve human health. Experimental studies showed that flavonoids have the capacity to alter physiological processes as well as cellular and molecular mechanisms associated with their antioxidant properties. An important function of flavonoids was determined in the cardiovascular system, namely their capacity to lower blood pressure and to improve endothelial function. (−)-Epicatechin and taxifolin are two flavonoids with notable antihypertensive effects and multiple beneficial actions in the cardiovascular system, but they also possess antiviral effects, which may be of particular importance in the ongoing pandemic situation. Thus, this review is focused on the current knowledge of (−)-epicatechin as well as (+)-taxifolin and/or (−)-taxifolin-modified biological action and underlining molecular mechanisms determined in preclinical studies, which are relevant not only to the treatment of hypertension per se but may provide additional antiviral benefits that could be relevant to the treatment of hypertensive subjects with SARS-CoV-2 infection.
... This receptor is found in endothelial cells that line blood vessels. Interaction with SARS-CoV2 can lead to activation of coagulation cascades, leading to the respective coagulation abnormalities seen in severe cases of COVID19 [19]. ...
Article
Introduction COVID19 has raised concerns for resource allocation across various sectors of healthcare. At the frontlines, emergency departments are required to triage a wide range of acuity and non-specific symptomology. Methods This retrospective study aimed to pave the way for more concrete detection and triage of patients by analyzing symptomology, physical findings, diagnostic testing and relevant hospital course of the 458 suspected cases that initially presented to an academic level one trauma center emergency department between March and August 2020. A total of 202 COVID positive cases were analyzed. Results The most common symptoms were cough (70.63%), fatigue (77%), and shortness of breath (59%). There was a significantly higher percentage of abnormal chest imaging in inpatient groups compared to the ED discharge group (42.86% vs 79%, p < 0.01). Laboratory studies, especially markers of inflammation (CRP, ESR), markers of tissue damage (lactic acid, troponin), and markers of infection were markedly higher and above normal reference ranges in complicated cases (p < 0.01). While there is limited data on the sensitivity and specificity of the current nasopharyngeal PCR test, there was no permutation of symptoms, physical findings, diagnostic testing that was more sensitive than that of the current PCR test calculated at 66.1% in our cohort. Conclusion Laboratory studies that otherwise are more commonly conducted inpatient, including markers of inflammation, tissue damage, and infection, may be useful in disposition planning of ED patients in conjunction with clinical correlation of presentation and chest imaging.
... Among others, ACE2-deficient mice showed increased levels of proatherogenic mediators with an impaired endothelium-dependent relaxation that was attenuated by the blockade of angiotensin 1-7; while the overexpression of ACE2 in human endothelial cells stimulated endothelial cell migration and limited the expression of monocyte and cellular adhesion molecules. 11,12 Moreover, the inhibition of ACE2 in atherosclerosis-prone apolipoprotein E-deficient mice increased the proatherogenic effect of a high-fat diet. 13 Some authors have speculated that the binding of the virus to the receptor could reduce the amount of ACE2 accessible for Ang II, with a downregulation of the AT2R-mediated response ( Figure 2). ...
Article
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The renin–aldosterone–angiotensin system (RAAS) plays an important role in the pathogenesis of coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for SARS-CoV-2 and the host’s expression of this membrane-bound protein could affect susceptibility to infection. The RAAS is an important regulator of cardiovascular physiology and ACE2 has an essential role. People with hypertension and other traits have shown to have an imbalance in ACE/ACE2 levels and reduced levels of ACE2 could enhance the risk of adverse outcome in patients with COVID-19. It has been hypothesised that the RAAS may mediate the interplay between cardiovascular disease and COVID-19 severity. Evidence shows that antihypertensive drugs that target the RAAS have no significant effect on the risk of infection and disease outcome. Variations in RAAS genes have been associated with the risk of developing hypertension and cardiovascular disease and could partly explain the heterogenous response to SARS-CoV-2 infection. This article explores the interplay between the RAAS and COVID-19, with emphasis on the possible relationship between genetic variations and disease severity.
... When compared with couples that include normozoospermic 303 males, azoospermia causes a decrease in the quality of sexual 304 function and a significant level of psychological distress. 98 In 305 fact, healthcare professionals are exposed to psychological importantly, it is known that ACE2 is expressed by the endothe-326 lium, 106 and is the protein which the virus uses to access host 327 cells. 107 It has also been hypothesized that pulmonary fibrosis The effects of SARS-CoV-2 on male erectile function. ...
Article
Throughout 2021, the scientific and medical communities were concentrated on dealing with the acute morbidity and mortality induced by the COVID-19 pandemic due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We reviewed the present data for adverse effects of COVID-19 on the different parts of the male urogenital system during the dynamic situation of the COVID-19 pandemic. With the approval of COVID-19 vaccinations, there is a ray of hope at the end of this dark tunnel and a chance to look ahead for the management of long-term consequences in males with urogenital illnesses. A multidisciplinary investigation of these cases could provide information for establishing and optimizing treatment protocols. Teaser: COVID-19 is more severe and lethal in male patients, probably due to gender-specific alterations in ACE2 receptor expression. Furthermore, COVID-19 has adverse effects on the reproductive system, sexual and bladder functions, and prostate pathologies.
... Apart from respiratory manifestations, thrombosis and pulmonary embolism are presentations of severe SARS-CoV-19 infection (46). This can be explained by the endothelial injury caused by the virus, as endothelial cells also express ACE2 (47). Endothelial injury induces high vascular permeability and facilitates viral invasion. ...
Article
Purpose: The novel coronavirus disease 2019 (COVID-19) has raised a global public health concern. The purpose of this review is to summarize the evidence currently available on COVID-19 for its ocular implications and manifestations from both pathogenetic and clinical standpoints. Methods: For this narrative review, more than 100 relevant scientific articles were considered from various databases (PubMed, Google Scholar, and Science Direct) using keywords such as coronavirus outbreak, COVID-19, ophthalmology, ocular symptoms. Results:Daily healthcare both from patient and physician perspective, as well as on some guidelines regarding prevention and management have dramatically changed over the last few months. Although COVID-19 infection mainly affects the respiratory system as well as the gastrointestinal, cardiovascular, and urinary systems, it may cause a wide spectrum of ocular manifestations. Various challenges have to be faced to minimize exposure for both patients and physicians. Conclusion:The risk of COVID-19 infection should be considered and medical care should be prioritized for urgent cases. Appropriate management for patients with chronic cases that may result in adverse outcomes should not be neglected, while patients that can be monitored remotely should be identified.
... Hence, the ACE2 system acts as a preventive mechanism against MI, hypertension, lung disease, and diabetic complications [82]. Earlier studies suggested that there is a substantial expression of ACE2 receptor within the heart tissue cells including cardiomyocytes [83], cardiac myofibroblasts [84], and endothelial cells [85] and that it has a protective role against cardiac damage [86]. In a murine model of SARS-CoV infection, ACE2 expression was reduced, which led to an increase in angiotensin II levels and hence increased vascular permeability and respiratory complications, which were reversed by treatment with recombinant ACE2 or an ARB (losartan) [87]. ...
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The rapid spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID‐19), has had a dramatic negative impact on public health and economies worldwide. Recent studies on COVID-19 complications and mortality rates suggest that there is a higher prevalence in cardiovascular diseases (CVD) patients. Past investigations on the associations between pre-existing CVDs and susceptibility to coronavirus infections including SARS‐CoV and the Middle East Respiratory Syndrome coronavirus (MERS-CoV), have demonstrated similar results. However, the underlying mechanisms are poorly understood. This has impeded adequate risk stratification and treatment strategies for CVD patients with SARS-CoV-2 infections. Generally, dysregulation of the expression of angiotensin‐converting enzyme (ACE) and the counter regulator, angiotensin‐converting enzyme 2 (ACE2) is a hallmark of cardiovascular risk and CVD. ACE2 is the main host receptor for SARS-CoV-2. Although further studies are required, dysfunction of ACE2 after virus binding and dysregulation of the renin-angiotensin-aldosterone system (RAAS) signaling may worsen the outcomes of people affected by COVID-19 and with preexisting CVD. Here, we review the current knowledge and outline the gaps related to the relationship between CVD and COVID-19 with a focus on the RAAS. Improved understanding of the mechanisms regulating viral entry and the role RAAS may direct future research with the potential to improve the prevention and management of COVID-19.
... Ang II produces ROS by stimulating membrane-bound NADPH oxidase [25]. In consequence, Ang II degradation into Ang 1-7 by ACE2 mitigates oxidative stress as it inhibits NADPH oxidase [26]. Indeed, ACE2 bounding to the virus downregulates ACE2, leading to an increased presence of superoxide species and subsequent cell damage, which may include lipid peroxidation, protein carbonylation and DNA oxidation [27], establishing an oxidative stress cycle, and ultimately, increasing the risk of suffering severe COVID-19 illness forms [25]. ...
Article
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Background: Oxidative stress may be a key player in COVID-19 pathogenesis due to its significant role in response to infections. A defective redox balance has been related to viral pathogenesis developing a massive induction of cell death provoked by oxidative stress. The aim of this study is to perform a complete oxidative stress profile evaluation regarding antioxidant enzymes, total antioxidant capacity and oxidative cell damage in order to characterize its role in diagnosis and severity of this disease. Methods: Blood samples were obtained from 108 COVID-19 patients and 28 controls and metabolites representative of oxidative stress were assessed. The association between lipid peroxidation and 28-day intubation/death risk was evaluated by multivariable regression analysis. Probability of intubation/death to day-28 was analyzed by using Kaplan-Meier curves and tested with the log-rank test. Results: Antioxidant enzymes (Superoxide dismutase (SOD) and Catalase) and oxidative cell damage (Carbonyl and Lipid peroxidation (LPO)) levels were significantly higher in COVID-19 patients while total antioxidant capacity (ABTS and FRAP) levels were lower in these patients. The comparison of oxidative stress molecules' levels across COVID-19 severity revealed that only LPO was statistically different between mild and intubated/death COVID-19 patients. COX multivariate regression analysis identified LPO levels over the OOP (LPO>1948.17 μM) as an independent risk factor for 28-day intubation/death in COVID-19 patients [OR: 2.57; 95% CI: 1.10-5.99; p = 0.029]. Furthermore, Kaplan-Meier curve analysis revealed that COVID-19 patients showing LPO levels above 1948.17 μM were intubated or died 8.4 days earlier on average (mean survival time 15.4 vs 23.8 days) when assessing 28-day intubation/death risk (p < 0.001). Conclusion: These findings deepen our knowledge of oxidative stress status in SARS-CoV-2 infection, supporting its important role in COVID-19. In fact, higher lipid peroxidation levels are independently associated to a higher risk of intubation or death at 28 days in COVID-19 patients.
... Measuring vascular endothelial function can thus help predict severe conditions in high-risk patients with COVID-19 [26,27]. Animal studies have shown that overexpression of ACE2 contributes to endothelial protection, thus contributing to atherosclerosis [28,29]. In addition, ACE2 can be used as a regulatory factor in heart failure and can regulate cardiac function by counterbalancing the function of ACE or by Ang1-7 and Apelin. ...
Article
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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells mainly by the angiotensin converting enzyme 2 (ACE2) receptor, which can recognize the spike (S) protein by its extracellular domain. Previously, recombinant soluble ACE2 (sACE2) has been clinically used as a therapeutic treatment for cardiovascular diseases. Recent data demonstrated that sACE2 can also be exploited as a decoy to effectively inhibit the cell entry of SARS-CoV-2, through blocking SARS-CoV-2 binding to membrane-anchored ACE2. In this study, we summarized the current findings on the optimized sACE2-based strategies as a therapeutic agent, including Fc fusion to prolong the half-life of sACE2, deep mutagenesis to create high-affinity decoys for SARS-CoV-2, or designing the truncated functional fragments to enhance its safety, among others. Considering that COVID-19 patients are often accompanied by manifestations of cardiovascular complications, we think that administration of sACE2 in COVID-19 patients may be a promising therapeutic strategy to simultaneously treat both cardiovascular diseases and SARS-CoV-2 infection. This review would provide insights for the development of novel therapeutic agents against the COVID-19 pandemic.
... Another important implication here is that this VE single continuous monolayer of cells pervades through the entire body of the individual, connecting the blood, lungs, heart, liver, kidney, brain, and other metabolic niches. Consequently, the VE serves as the link connecting various cardiometabolic, pulmonary, septic, and renal diseases [30] . Indeed, its involvement in neuronal pathology has been implicated as well [18 , 38 , 47] . ...
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COVID-19 is caused by infection with the “severe acute respiratory syndrome coronavirus-2” (i.e., SARS-CoV-2). This is an enveloped virus having a positive sense, single-stranded RNA genome; like the two earlier viruses SARS-CoV and the Middle East respiratory syndrome (MERS) virus. COVID-19 is unique in that, in the severe case, it has the propensity to affect multiple organs, leading to multiple organ distress syndrome (MODS), and causing high morbidity and mortality in the extreme case. In addition, comorbidities like age, cardiovascular disease, diabetes and its complications, obesity, are risk factors for severe COVID-19. It turns out that a most plausible, simple, single explanation for this propensity for MODS is the pivotal involvement of the vascular endothelium (VE). This is a consequence of the fact that the VE seamlessly connects all the entire vascular bed in the body, thus linking all the target organs (heart, lungs, kidney, liver, brain) and systems. Infection with SARS-CoV-2 leads to hyper-inflammation yielding uncontrolled production of a mixture of cytokines, chemokines, reactive oxygen species, nitric oxide, oxidative stress, acute phase proteins (e.g., C-reactive protein), and other pro-inflammatory substances. In the extreme case, a cytokine storm is created. Displacement of the virus bound to the VE, and/or inhibition of binding of the virus, would constitute an effective strategy for preventing COVID-19. In this regard, the acetone-water extract of the leaf of the Neem (Azadirachta indica) plant has been known to prevent the adherence of malaria parasitized red blood cells (pRBCs) to VE; prevent cytoadherence of cancer cells in metastasis; and prevent HIV from invading target T lymphocytes. We therefore hypothesize that this Neem leaf acetone-water extract will prevent the binding of SARS-CoV-2 to the VE, and therefore be an effective therapeutic formulation against COVID-19. It is therefore advocated herein that this extract be investigated through rigorous clinical trials for this purpose. It has the advantages of being (i) readily available, and renewable in favour of the populations positioned to benefit from it; (ii) simple to prepare; and (iii) devoid of any detectable toxicity.
... Apart from respiratory manifestations, thrombosis and pulmonary embolism are presentations of severe SARS-CoV-19 infection (46). This can be explained by the endothelial injury caused by the virus, as endothelial cells also express ACE2 (47). Endothelial injury induces high vascular permeability and facilitates viral invasion. ...
... As lung blood capillary vessels are damaged, there is a strong possibility that SARS-CoV-2 enters the bloodstream at this site. ACE2 receptors are also found in the endothelium in vessels [24]. We suspect that what is considered coagulation disorders may be ACE2 receptors in the endothelium being attacked by the SARS-CoV-2, thereby generating coagulum in order to "cover" the endothelial lesions [25]. ...
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Background: Critical hypoxia in this COVID-19 pandemic results in high mortality and economic loss worldwide. Initially, this disease' pathophysiology was poorly understood and interpreted as a SARS (Severe Acute Respiratory Syndrome) pneumonia. The severe atypical lung CAT scan images alerted all countries, including the poorest, to purchase lacking sophisticated ventilators. However, up to 88% of the patients on ventilators lost their lives. It was suggested that COVID-19 could be similar to a High-Altitude Pulmonary Edema (HAPE). New observations and pathological findings are gradually clarifying the disease. Methods: As high-altitude medicine and hypoxia physiology specialists working and living in the highlands for over 50 years, we perform a perspective analysis of hypoxic diseases treated at high altitudes and compare them to Covid-19. Oxygen transport physiology, SARS-Cov-2 characteristics , and its transmission, lung imaging in COVID-19, and HAPE, as well as the causes of clinical signs and symptoms, are discussed. Results: High-altitude oxygen transport physiology has been systematically ignored. COVID-19 signs and symptoms indicate a progressive and irreversible failure in the oxygen transport system, secondary to pneumolysis produced by SARS-Cov-2's alveolar-capillary membrane "attack". HAPE's pulmonary compromise is treatable and reversible. COVID-19 is associated with several diseases, with different individual outcomes, in different countries, and at different altitudes. Conclusions: The pathophysiology of High-altitude illnesses can help explain COVID-19 patho-physiology, severity, and management. Early diagnosis and use of EPO, acetylsalicylic-acid, and other anti-inflammatories, oxygen therapy, antitussives, antibiotics, and the use of Earth open-circuit astronaut resembling suits to return to daily activities, should all be considered. Ventilator use can be counterproductive. Immunity development is the only feasible long-term survival tool.
... Thus, while Ang II evokes vasoconstrictive, proliferative, and angiogenic effects, Ang 1-7 elicits anti-proliferative, anti-angiogenic, and vasodilator functions (Bharadwaj et al., 2011). Moreover, ACE2 has a protective effect on the endothelium and improves endothelial function, apparently mediated by Ang 1-7 production (Lovren et al., 2008;Fraga-Silva et al., 2013; Figure 1). The relevance of ACE2 has been confirmed in animals deficient in this enzyme. ...
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In December 2019, the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) rapidly spread to become a pandemic. To date, increasing evidence has described the potential negative impact of SARS-CoV-2 infection on pregnant women. Although the pathophysiology of coronavirus disease 2019 (COVID-19) is not entirely understood, there is emerging evidence that it causes a severe systemic inflammatory response associated with vascular alterations that could be of special interest considering some physiological changes in pregnancy. Additionally, these alterations may affect the physiology of the placenta and are associated with pregnancy complications and abnormal histologic findings. On the other hand, data about the vaccine against SARS-CoV-2 are limited, but the risks of administering COVID- 19 vaccines during pregnancy appear to be minimal. This review summarizes the current literature on SARSCoV2 virus infection, the development of COVID-19 and its relationship with physiological changes, and angiotensin-converting enzyme 2 (ACE2) function during pregnancy. We have particularly emphasized evidence coming from Latin American countries.
... On the other hand, ACE2 counterbalances Ang II-AT1R effects by either stimulating an alternative pathway for Ang I degradation to produce Ang-(1-9), or by inactivating Ang II and hydrolyzing it to a heptapeptide Ang-(1-7). The latter stimulates vasodilation and activates anti-inflammatory, antifibrotic, and antithrombotic cascades via the MasR axis [59,60], as well as the protection of endothelial cell activity [57,58]. ...
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The binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein to its cellular receptor, the angiotensin-converting enzyme 2 (ACE2), causes its down-regulation, which subsequently leads to the dysregulation of the renin-angiotensin system (RAS) in favor of the ACE-angiotensin II (Ang II)-angiotensin II type I receptor (AT1R) axis. AT1R has a major role in RAS by being involved in several physiological events including blood pressure control and electrolyte balance. Following SARS-CoV-2 infection, pathogenic episodes generated by the vasoconstriction, proinflammatory, profibrotic, and prooxidative consequences of the Ang II-AT1R axis activation are accompanied by a hyperinflammatory state (cytokine storm) and an acute respiratory distress syndrome (ARDS). AT1R, a member of the G protein-coupled receptor (GPCR) family, modulates Ang II deleterious effects through the activation of multiple downstream signaling pathways, among which are MAP kinases (ERK 1/2, JNK, p38MAPK), receptor tyrosine kinases (PDGF, EGFR, insulin receptor), and nonreceptor tyrosine kinases (Src, JAK/STAT, focal adhesion kinase (FAK)), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. COVID-19 is well known for generating respiratory symptoms, but because ACE2 is expressed in various body tissues, several extrapulmonary pathologies are also manifested, including neurologic disorders, vasculature and myocardial complications, kidney injury, gastrointestinal symptoms, hepatic injury, hyperglycemia, and dermatologic complications. Therefore, the development of drugs based on RAS blockers, such as angiotensin II receptor blockers (ARBs), that inhibit the damaging axis of the RAS cascade may become one of the most promising approaches for the treatment of COVID-19 in the near future. We herein review the general features of AT1R, with a special focus on the receptor-mediated activation of the different downstream signaling pathways leading to specific cellular responses. In addition, we provide the latest insights into the roles of AT1R in COVID-19 outcomes in different systems of the human body, as well as the role of ARBs as tentative pharmacological agents to treat COVID-19.
... However, other symptoms such as thrombosis, pulmonary embolism, and high blood pressure have been reported as well, suggesting that the virus targets the endothelium (5,6). It is well known that ACE-2 is also expressed in endothelial cells (7,8). Additionally, dysregulated immune responses, as those observed in COVID-19, are a major culprit in endothelial dysfunction, since they alter microvascular permeability and induce vascular inflammation (6). ...
Article
Several organs, such as the heart, breasts, intestine, testes, and ovaries, have been reported to be target tissues of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To date, no studies have demonstrated SARS-CoV-2 infection in the female reproductive system. In the present study, we investigated the effects of SARS-CoV-2 infection on ovarian function by comparing follicular fluid (FF) from control and recovered coronavirus disease 2019 (COVID-19) patients and by evaluating the influence of these FF on human endothelial and non-luteinized granulosa cell cultures. Our results showed that most FFs (91.3%) from screened post COVID-19 patients were positive for IgG antibodies against SARS-CoV-2. Additionally, patients with higher levels of IgG against SARS-CoV-2 had lower numbers of retrieved oocytes. While VEGF and IL-1β were significantly lower in post COVID-19 FF, IL-10 did not differ from that in control FF. Moreover, in COV434 cells stimulated with FF from post COVID-19 patients, steroidogenic acute regulatory protein (StAR), estrogen-receptor β (Erβ), and vascular endothelial growth factor (VEGF) expression were significantly decreased, whereas estrogen-receptor α (ERα) and 3β-hydroxysteroid dehydrogenase (3β-HSD) did not change. In endothelial cells stimulated with post COVID-19 FF, we observed a decrease in cell migration without changes in protein expression of certain angiogenic factors. Both cell types showed a significantly higher γH2AX expression when exposed to post COVID-19 FF. In conclusion, our results describe for the first time that the SARS-CoV-2 infection adversely affects the follicular microenvironment, thus dysregulating ovarian function.
... 72 ). Increased ACE2 can exert a protective role in limiting excessive vascular dysfunction 99 , but, at the same time, would render endothelial cells more susceptible to direct viral infection. ...
Article
Coronavirus disease 2019 (COVID-19) is a consequence of infection of the upper and lower respiratory tract with severe acute respiratory syndrome coronavirus 2 but often becomes a systemic disease, with important involvement of other organs. A bidirectional relationship exists between COVID-19 and cardiovascular disease. On the one hand, preexisting comorbidities, in particular high prevalence of cardiovascular risk factors such as hypertension and diabetes and chronic cardiovascular conditions predispose to severe disease. On the other hand, biomarkers of myocardial injury are frequently raised in patients with COVID-19, along with arrhythmia and heart failure. Localized thrombosis is a common finding in the lungs but can also increase the occurrence of thrombotic events systemically. Thrombosis is consequent to different pathogenic mechanisms, which include endothelial dysfunction and immunothrombosis. Thrombocytopenia is common in patients with COVID-19 and alterations in platelet function participate in the pro-thrombotic phenotype. Involvement of the cardiovascular system in COVID-19 has important consequences during recovery from infection and the development of long COVID. Mauro Giacca and Ajay M. Shah discuss the most recent advances in the bidirectional relationship between COVID-19 and an array of cardiovascular diseases.
... In addition, activation of Mas receptors leads to the release of nitric oxide (NO), a well-known vasodilator [4,5]. Generally, ACE2-mediated mechanisms participate in the maintenance of normal endothelium-dependent relaxation, and endothelial dysfunction is reversed in ACE2-knockout mice [6] to promote endothelial dysfunction and inflammation [7]. Since binding of the SARS-CoV-2 virus to transmembrane ACE2 could result in dysfunction of Mas receptor-mediated pathways in the vasculature, it is crucial to reveal the role of ACE2 inhibitor-treatment, especially within pre-existing cardiovascular pathologies. ...
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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infects host cells through angiotensin-converting enzyme 2 (ACE2). Concurrently, the product of ACE2 action, angiotensin 1–7 (Ang 1–7), binds to Mas receptors within the cardiovascular system and provides protective effects. Therefore, it is crucial to reveal the role of ACE2 inhibition, especially within pre-existing cardiovascular pathologies. In our study, we imitated the action of SARS-CoV-2 in organisms using the low dose of the ACE2 inhibitor MLN-4760 with the aim of investigating to what degree ACE2 inhibition is detrimental to the cardiovascular system of spontaneously hypertensive rats (SHRs), which represent a model of human essential hypertension. Our study revealed the complex action of MLN-4760 in SHRs. On the one hand, we found that MLN-4760 had 1) (pro)obesogenic effects that negatively correlated with alternative renin-angiotensin system activity and Ang 1–7 in plasma, 2) negative effects on ACE1 inhibitor (captopril) action, 3) detrimental effects on the small arteries function and 4) anti-angiogenic effect in the model of chick chorioallantoic membrane. On the other hand, MLN-4760 induced compensatory mechanisms involving strengthened Mas receptor-, nitric oxide- and hydrogen sulfide-mediated signal transduction in the aorta, which was associated with unchanged blood pressure, suggesting beneficial action of MLN-4760 when administered at a low dose.
... ACE2 in SARS-CoV-infected cells has been shown to be also involved in postinfection regulation, including immune response, viral genome replication, and cytokine secretion [61]. A previous study demonstrated that overexpression of ACE2 prevents Ang II-induced Nox2 expression and ROS generation in endothelium [62]. In healthy individuals, ACE2 supports lung homeostasis via the production of angiotensin 1-7 and controls inflammation and blood pressure. ...
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The COVID-19 pandemic caused relatively high mortality in patients, especially in those with concomitant diseases (i.e., diabetes, hypertension, and chronic obstructive pulmonary disease (COPD)). In most of aforementioned comorbidities, the oxidative stress appears to be an important player in their pathogenesis. The direct cause of death in critically ill patients with COVID-19 is still far from being elucidated. Although some preliminary data suggests that the lung vasculature injury and the loss of the functioning part of pulmonary alveolar population are crucial, the precise mechanism is still unclear. On the other hand, at least two classes of medications used with some clinical benefits in COVID-19 treatment seem to have a major influence on ROS (reactive oxygen species) and RNS (reactive nitrogen species) production. However, oxidative stress is one of the important mechanisms in the antiviral immune response and innate immunity. Therefore, it would be of interest to summarize the data regarding the oxidative stress in severe COVID-19. In this review, we discuss the role of oxidative and antioxidant mechanisms in severe COVID-19 based on available studies. We also present the role of ROS and RNS in other viral infections in humans and in animal models. Although reactive oxygen and nitrogen species play an important role in the innate antiviral immune response, in some situations, they might have a deleterious effect, e.g., in some coronaviral infections. The understanding of the redox mechanisms in severe COVID-19 disease may have an impact on its treatment.
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Cell invasion mediated by angiotensin-converting enzyme 2 (ACE2) ectoenzyme and cellular proteases, such as trypsin-like proteases, cathepsins, transmembrane serine protease 2 and furin, target different tissues and organs as lung, gut, colon, ileum, kidney, gallbladder, heart muscle, epididymis, breast, ovary, stomach, bile duct, liver, oral cavity, lung, thyroid, esophagus, bladder, breast, uterus, prostate, pancreas, cerebellum, as well as calyx secreting cells in the nasal and sinus tissue. Loss of homeostasis of the renin-angiotensin system deregulates different axes compromising metabolic, cardiorespiratory, renal and hepatic control. SARS-CoV-2 infected cell undergoes pyroptosis and releases molecular patterns associated with damage: pro-inflammatory interleukin (IL)-1, IL-6, IL-8, IL-10, IL-17, induced protein-10, interferon gamma, interferon gamma-induced protein-10, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, macrophage inflammatory protein 1α and 1β, monocyte chemotherapy activating protein 1, inflammatory macrophage protein 1, tumor necrosis-α, and mediators of immune-mediated inflammatory diseases. Cytokine storm and non-neutralizing antibodies produced by B cells circulate, cause/exacerbate damage to various organs. During viral replication and low oxygen saturation, loss of HIF-mediated cell homeostasis can lead to cell death/lysis and tissue damage, related to the hyperinflammatory response. The SARS-CoV-2-ACE2 can increase permeability, inflammation and microbial transmission by bacteremia or endotoxemia, in addition to dysbiosis. Thrombotic potential and the immunoinflammatory imbalance compromise function or lead to injuries and multiple organ failure. Infection by SARS-CoV-2 has the potential to modify the natural history of diseases, the relationships or interactions between the different systems and pathologies and the effects of their treatments, as in periodontal medicine approach.
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Jiedu Huoxue Decoction (JHD), a recommended traditional prescription for patients with severe COVID-19, has appeared in the treatment protocols in China. Based on bioinformatics and computational chemistry methods, including molecular docking, molecular dynamics (MD) simulation, and Molecular Mechanics Generalized Born Surface Area (MM/GBSA) calculation, we aimed to reveal the mechanism of JHD in treating severe COVID-19. The compounds in JHD were obtained and screened on TCMSP, SwissADME, and ADMETLab platforms. The compound targets were obtained from TCMSP and STITCH, while COVID-19 targets were obtained from Genecards and NCBI. The protein-protein interaction network was constructed by using STRING. Gene Ontology (GO) and KEGG enrichment were performed with ClueGO and R language. AutoDock vina was employed for molecular docking. 100 ns MD simulation of the optimal docking complex was carried out with AmberTools 20. A total of 84 compounds and 29 potential targets of JHD for COVID-19 were collected. The key phytochemicals included quercetin, luteolin, β-sitosterol, puerarin, stigmasterol, kaempferol, and wogonin, which could regulate the immune system. The hub genes included IL6, IL10, VEGFA, IL1B, CCL2, HMOX1, DPP4, and ACE2. ACE2 and DPP4 were related to SARS-CoV-2 entering cells. GO and KEGG analysis showed that JHD could intervene in cytokine storm and endothelial proliferation and migration related to thrombosis. The molecular docking, 100 ns MD simulation, and MM/GBSA calculation confirmed that targets enriched in the COVID-19 pathway had high affinities with related compounds, and the conformations of the puerarin-ACE2, quercetin-EGFR, luteolin-EGFR, and quercetin-IL1B complexes were stable. In a word, JHD could treat COVID-19 by intervening in cytokine storm, thrombosis, and the entry of SARS-CoV-2, while regulating the immune system. These mechanisms were consistent with JHD's therapeutic concept of “detoxification” and “promoting blood circulation and removing blood stasis” in treating COVID-19. The research provides a theoretical basis for the development and application of JHD.
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The etiological agent of COVID-19 SARS-CoV-2, is primarily a pulmonary-tropic coronavirus. Infection of alveolar pneumocytes by SARS-CoV-2 requires virus binding to the angiotensin I converting enzyme 2 (ACE2) monocarboxypeptidase. ACE2, present on the surface of many cell types, is known to be a regulator of blood pressure homeostasis through its ability to catalyze the proteolysis of Angiotensin II (Ang II) into Angiotensin-(1-7) [Ang-(1-7)]. We therefore hypothesized that SARS-CoV-2 could trigger variations of ACE2 expression and Ang II plasma concentration in SARS-CoV-2-infected patients. We report here, that circulating blood cells from COVID-19 patients express less ACE2 mRNA than cells from healthy volunteers. At the level of circulating cells, this ACE2 gene dysregulation mainly affects the monocytes, which also show a lower expression of membrane ACE2 protein. Moreover, soluble ACE2 (sACE2) plasma concentrations are lower in prolonged viral shedders than in healthy controls, while the concentration of sACE2 returns to normal levels in short viral shedders. In the plasma of prolonged viral shedders, we also found higher concentrations of Ang II and angiotensin I (Ang I). On the other hand, the plasma levels of Ang-(1-7) remains almost stable in prolonged viral shedders but seems insufficient to prevent the adverse effects of Ang II accumulation. Altogether, these data evidence that the SARS-CoV-2 may affect the expression of blood pressure regulators with possible harmful consequences on COVID-19 outcome.
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Endothelial cells (ECs) play a crucial role in the development and propagation of the severe COVID-19 stage as well as multiorgan dysfunction. It remains, however, controversial whether COVID-19-induced endothelial injury is caused directly by the infection of ECs with SARS-CoV-2 or via indirect mechanisms. One of the major concerns is raised by the contradictory data supporting or denying the presence of ACE2, the SARS-CoV-2 binding receptor, on the EC surface. Here, we show that primary human pulmonary artery ECs possess ACE2 capable of interaction with the viral Spike protein (S-protein) and demonstrate the crucial role of the endothelial glycocalyx in the regulation of the S-protein binding to ACE2 on ECs. Using force spectroscopy method, we directly measured ACE2- and glycocalyx-dependent adhesive forces between S-protein and ECs and characterized the nanomechanical parameters of the cells exposed to S-protein. We revealed that the intact glycocalyx strongly binds S-protein but screens its interaction with ACE2. Reduction of glycocalyx layer exposes ACE2 receptors and promotes their interaction with S-protein. These results indicate that the susceptibility of ECs to COVID-19 infection may depend on the glycocalyx condition.
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The review presents the data on characteristic features of the new coronavirus infection caused by SARS-CoV-2 and the possibility of its transmission through the eye surface and lacrimal fluid, analyzes the information on eye damage caused by COVID-19, and provides the results of a systematic meta-analysis on the subject. The author describes the system for organizing ophthalmological care in the settings of unfavorable epidemiological situation associated with the COVID-19 pandemic, and considers the preventive measures of infection transmission between patients and medical personnel. The article also gives recommendations for sterilizing medical equipment.
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Since the outbreak of the COVID-19, up to now, infection cases have been continuously rising to over 200 million around the world. Male bias in morbidity and mortality has emerged in the COVID-19 pandemic. The infection of SARS-CoV-2 has been reported to cause the impairment of multiple organs that highly express the viral receptor angiotensin-converting enzyme 2 (ACE2), including lung, kidney, and testis. Adverse effects on the male reproductive system, such as infertility and sexual dysfunction, have been associated with COVID-19. This causes a rising concern among couples intending to have a conception or who need assisted reproduction. To date, a body of studies explored the impact of SARS-CoV-2 on male reproduction from different aspects. This review aims to provide a panoramic view to understand the effect of the virus on male reproduction and a new perspective of further research for reproductive clinicians and scientists.
Chapter
On December 31, 2019, “an unknown viral pneumonia” was initially noticed in Wuhan, China. Since December 2019, the epidemic that started in Wuhan, China has spread quickly over an extensive field [1]. On January 10, 2020, a recent type of coronavirus genome was isolated from a patient’s tracheal secretion. Then, the World Health Organization (WHO) temporarily named the virus “2019 novel Coronavirus” [2, 3]. The disease was included in “Class B infectious diseases” by “National Health Commission of the People’s Republic of China” on January 20, 2020 [4]. This new agent formally clept as “SARS-CoV-2 infection Coronavirus Disease 2019 (COVID-19)” and “Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)” by WHO on February 11, 2020. WHO described this as a “Public Health Emergency of International Concern (PHEIC)” [5].
Chapter
COVID-19 represents a major challenge for researchers worldwide. Although the fine mechanisms that lead to the cell and tissue damage in patient infected by SARS-CoV-2 and that develop the disease are still unknown, the global effort to find a cure brought scientists worldwide to produce a considerable number of publications that are slowly disclosing how the virus works and how the human body responds to the infection. The development of the disease, in fact, seems to be related to both a direct damage of the virus on the cell or on particular structures in the tissue and how the immune system and the inflammatory process respond to the infection. Of particular interest is the finding of a peculiar feature of the disease leading to intussusceptive angiogenesis in the lungs of deceased patients that might represent an anatomopathological fingerprint of the same infection.
Article
Backgrounds Identification of a new axis of angiotensin converting enzyme 2 (ACE2)/angiotensin (1–7)/Mas receptor, in the renin-angiotensin system (RAS), has opened a new insight regarding the role of RAS and angiotensin in higher brain functions. ACE 2 catabolizes angiotensin II and produces angiotensin (1-7), an agonist of Mas receptor. Mice lacking the Mas receptor (angiotensin1-7 receptor) exhibit anxiety-like behaviors. The present study was conducted to test the hypothesis of the involvement of ACE2 genetic variant (G8790A) on response to Selective Serotonin Reuptake Inhibitors (SSRIs). Methods In a randomized control trial, two hundred newly diagnosed Iranian patients with major depressive disorder (MDD) completed 6 weeks of fluoxetine or sertraline treatment. Patients with a reduction of 50% or more in the Hamilton Rating Scale for Depression (HAM-D) score were considered responsive to treatment. G8790A polymorphism was determined in extracted DNAs using restriction fragment length polymerase chain reaction (PCR-RFLP) method. Results The A allele as well as AA and GA genotypes were significantly associated with better response to SSRIs (P=0.008; OR= 3.4; 95%CI=1.4-8.5 and P=0.027; OR=3.3, 95%CI=1.2-9.2 respectively). Moreover, patients with GA and AA genotypes responded significantly better to sertraline (P=0.0002; OR=9.1; 95%CI=2.4-33.7). The A allele was significantly associated with better response to sertraline (P=0.0001; OR=7.6; 95%CI=2.5-23.3). Conclusions In conclusion our results confirm the role of G8790A in response to some SSRIs.
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Angiotensin-(1-7) [ANG-(1-7)], an endogenous bioactive peptide constituent of the renin-angiotensin system, acts as an inhibitory growth factor in vitro and in vivo. In this study, we evaluated whether the antiangiogenic effect of ANG-(1-7) in the mouse sponge model of angiogenesis might be receptor mediated and involved in the release of nitric oxide (NO). The hemoglobin content (microg/mg wet tissue) of 7-day-old sponge implants was used as an index of the vascularization and showed that daily injections of ANG-(1-7) (20 ng) inhibited significantly the angiogenesis in the implants relative to the saline-treated group. The specific receptor antagonist D-Ala(7)-ANG-(1-7); A-779 prevented ANG-(1-7)-induced inhibition of angiogenesis. The antiangiogenic effect was also abolished by pretreatment with NO synthase inhibitors aminoguanidine (1 mg/ml) or N(G)-nitro-L-arginine methyl ester (0.3 mg/ml). Selective AT1 and AT2 angiotensin-receptor antagonists and an angiotensin-converting enzyme inhibitor, in combination with ANG-(1-7) or alone, did not alter angiogenesis in the implants. These results establish that the regulation of the vascular tissue growth by ANG-(1-7) is associated with NO release by activation of an angiotensin receptor distinct from AT1 and AT2.
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Cardiovascular diseases are predicted to be the most common cause of death worldwide by 2020. Here we show that angiotensin-converting enzyme 2 (ace2) maps to a defined quantitative trait locus (QTL) on the X chromosome in three different rat models of hypertension. In all hypertensive rat strains, ACE2 messenger RNA and protein expression were markedly reduced, suggesting that ace2 is a candidate gene for this QTL. Targeted disruption of ACE2 in mice results in a severe cardiac contractility defect, increased angiotensin II levels, and upregulation of hypoxia-induced genes in the heart. Genetic ablation of ACE on an ACE2 mutant background completely rescues the cardiac phenotype. But disruption of ACER, a Drosophila ACE2 homologue, results in a severe defect of heart morphogenesis. These genetic data for ACE2 show that it is an essential regulator of heart function in vivo.
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The discovery of angiotensin-converting enzyme 2 (ACE-2) has revealed a far more complex enzymatic cascade that may influence the renin-angiotensin system within the kidney, specifically the expression of the functional products angiotensin II (Ang II) and Ang-(1-7). The regulation of this critical system involved in blood pressure control must now encompass the integral relationship of ACE and ACE-2 activities.
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Angiotensin-(1-7) is increased in the circulation during human pregnancy, but its functional role is unknown. Recent studies suggested that it opposes angiotensin II mediated vascular growth. Because angiogenesis is critical to normal embryonic development during human pregnancy, this study assessed the in vitro effects of angiotensin-(1-7) on human umbilical vein endothelial cell tube formation. The blocking effects of the angiotensin-(1-7) receptor antagonist, D-[Alanine7]-Ang-(1-7), and angiotensin II receptor AT1 and AT2 antagonists, losartan and PD123319, on tube formation were measured by counting tube branch points. Human umbilical vein endothelial cells were cultured in EGM-2 medium and treated with angiotensin-(1-7) (0.17 nM-17 microM) for 18 h. Angiotensin-(1-7) inhibited tube formation by 24% (P < 0.01) at all doses tested. Treatment with 1.7 microM angiotensin-(1-7) plus 17 microM D-[Alanine7]-Ang-(1-7) resulted in the reversal of angiotensin-(1-7) mediated inhibition of tube formation (P < 0.05). Losartan (17 microM) also reversed the angiotensin-(1-7) mediated inhibition of tube formation (P < 0.05). Tube formation was unaffected by PD123319. These results suggest that angiotensin-(1-7) has an anti-angiogenic effect on human umbilical vein endothelial cells through a unique AT(1-7) receptor that is sensitive to losartan, indicating that angiotensin-(1-7) may play an important role in the regulation of vascular growth in the placenta during pregnancy.
Article
Angiotensin-converting enzyme 2 (ACE2) is a recently discovered homologue of the key enzyme of the renin-angiotensin system, the angiotensin-converting enzyme. The ACE2 enzyme is mainly expressed in cardiac blood vessels and tubular epithelia of the kidneys. Together with ACE2's unique metallocarboxypeptidase activity, the restricted tissue distribution suggests a distinctive physiological function in blood pressure, blood flow and fluid regulation. The ace2 gene was mapped to quantitative trait loci affecting susceptibility to hypertension in rats. Furthermore, ACE2 appears to be a negative regulator of ACE in the heart. ACE2 messenger RNA and protein levels are substantially regulated in the kidney of diabetic and pregnant rats. The mechanism of ACE2 function and its physiologic significance are not yet fully understood; however, as ACE2 differs in its specificity and physiological role from ACE, this opens a new potential venue for drug discovery aimed at cardiovascular disease, hypertension and diabetic complications.
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Protein energy malnutrition (PEM) is often present in patients with chronic kidney disease with or without ongoing renal replacement therapy. Muscle wasting (sarcopenia) is one of the hallmarks of PEM in these patients and recent studies have reported a link between sarcopenia and inflammation. The low-grade inflammation often observed in end-stage renal disease (ESRD) can lead to sarcopenia through an increase in protein catabolism, a decrease in protein syntheses or both. The activation of the ATP-ubiquitin-proteasome pathway, insulin resistance, hypermetabolism, and decreased appetite are all plausible pathophysiological pathyways whereby inflammation can contribute to sarcopenia and PEM. In the present review we discuss these interactions between inflammation and wasting in ESRD patients and explore putative pathways involved in this condition.
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ACE2, the first known human homologue of angiotensin-converting enzyme (ACE), was identified from 5' sequencing of a human heart failure ventricle cDNA library. ACE2 has an apparent signal peptide, a single metalloprotease active site, and a transmembrane domain. The metalloprotease catalytic domains of ACE2 and ACE are 42% identical, and comparison of the genomic structures indicates that the two genes arose through duplication. In contrast to the more ubiquitous ACE, ACE2 transcripts are found only in heart, kidney, and testis of 23 human tissues examined. Immunohistochemistry shows ACE2 protein predominantly in the endothelium of coronary and intrarenal vessels and in renal tubular epithelium. Active ACE2 enzyme is secreted from transfected cells by cleavage N-terminal to the transmembrane domain. Recombinant ACE2 hydrolyzes the carboxy terminal leucine from angiotensin I to generate angiotensin 1-9, which is converted to smaller angiotensin peptides by ACE in vitro and by cardiomyocytes in culture. ACE2 can also cleave des-Arg bradykinin and neurotensin but not bradykinin or 15 other vasoactive and hormonal peptides tested. ACE2 is not inhibited by lisinopril or captopril. The organ- and cell-specific expression of ACE2 and its unique cleavage of key vasoactive peptides suggest an essential role for ACE2 in the local renin-angiotensin system of the heart and kidney. The full text of this article is available at http://www. circresaha.org.
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Use of the real-time polymerase chain reaction (PCR) to amplify cDNA products reverse transcribed from mRNA is on the way to becoming a routine tool in molecular biology to study low abundance gene expression. Real-time PCR is easy to perform, provides the necessary accuracy and produces reliable as well as rapid quantification results. But accurate quantification of nucleic acids requires a reproducible methodology and an adequate mathematical model for data analysis. This study enters into the particular topics of the relative quantification in real-time RT–PCR of a target gene transcript in comparison to a reference gene transcript. Therefore, a new mathematical model is presented. The relative expression ratio is calculated only from the real-time PCR efficiencies and the crossing point deviation of an unknown sample versus a control. This model needs no calibration curve. Control levels were included in the model to standardise each reaction run with respect to RNA integrity, sample loading and inter-PCR variations. High accuracy and reproducibility (<2.5% variation) were reached in LightCycler PCR using the established mathematical model.
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Angiotensin II (Ang II)-mediated induction of vascular superoxide anion formation could contribute to the development of endothelial dysfunction, hypertension, and atherosclerosis. An NAD(P)H oxidase has been identified as a major endothelial source of superoxide anions. However, the molecular mechanism underlying the regulation of NAD(P)H oxidase activity in response to Ang II is not well understood. We investigated the dose-dependent regulation of superoxide anion formation and of NAD(P)H oxidase subunit expression in response to Ang II in human endothelial cells. Ang II regulates superoxide anion formation and the limiting subunit of endothelial NAD(P)H oxidase, gp91-phox, in a dose-dependent manner via Ang II type 1 (AT1) receptor-mediated induction and Ang II type 2 receptor-mediated partial inhibition at higher Ang II concentrations. Furthermore, AT1 receptor blocker therapy before coronary bypass surgery downregulates the gp91-phox expression in internal mammary artery biopsies of patients with coronary artery disease. Our data support a dose-dependent induction of proatherosclerotic oxidative stress in human endothelial cells in response to Ang II. The expression of NAD(P)H oxidase subunit gp91-phox is critical for endothelial superoxide anion formation. AT1 receptor blockade has an antiatherosclerotic and antioxidative potential by the reduction of oxidative stress in the vessel wall.
Article
Angiotensin (Ang) peptides play a critical role in regulating vascular reactivity and structure. We showed that Ang-(1-7) reduced smooth muscle growth after vascular injury and attenuated the proliferation of vascular smooth muscle cells (VSMCs). This study investigated the molecular mechanisms of the antiproliferative effects of Ang-(1-7) in cultured rat aortic VSMCs. Ang-(1-7) caused a dose-dependent release of prostacyclin from VSMCs, with a maximal release of 277.9+/-25.2% of basal values (P<0.05) by 100 nmol/L Ang-(1-7). The cyclooxygenase inhibitor indomethacin significantly attenuated growth inhibition by Ang-(1-7). In contrast, neither a lipoxygenase inhibitor nor a cytochrome p450 epoxygenase inhibitor prevented the antiproliferative effects of Ang-(1-7). These results suggest that Ang-(1-7) inhibits vascular growth by releasing prostacyclin. Ang-(1-7) caused a dose-dependent release of cAMP, which might result from prostacyclin-mediated activation of adenylate cyclase. The cAMP-dependent protein kinase inhibitor Rp-adenosine-3',5'-cyclic monophosphorothioate attenuated the Ang-(1-7)-mediated inhibition of serum-stimulated thymidine incorporation. Finally, Ang-(1-7) inhibited Ang II stimulation of mitogen-activated protein kinase activities (ERK1/2). Incubation of VSMCs with concentrations of Ang-(1-7) up to 1 micromol/L had no effect on ERK1/2 activation. However, preincubation with increasing concentrations of Ang-(1-7) caused a dose-dependent reduction in Ang II-stimulated ERK1/2 activities. Ang-(1-7) (1 micromol/L) reduced 100 nmol/L Ang II-stimulated ERK1 and ERK2 activation by 42.3+/-6.2% and 41.2+/-4.2%, respectively (P<0.01). These results suggest that Ang-(1-7) inhibits vascular growth through the release of prostacyclin, through the prostacyclin-mediated production of cAMP and activation of cAMP-dependent protein kinase, and by attenuation of mitogen-activated protein kinase activation.
Article
At the present time, measures of endothelial cell function and biocompatibility have advanced our understanding of the pathophysiology of atherosclerosis and its treatment. They are quickly becoming well-established surrogates of disease activity; however, the ideal test(s) of endothelial function have yet to be established. As we incorporate new biomarkers into global risk assessment, the endothelium is the logical target of study, given its unique position as both a sensor and participant in the atherosclerosis process. Recent evidence suggests that the mechanistic basis for the powerful predictive value of inflammatory biomarkers such as CRP may also reside at the level of the endothelium. Although endothelial function testing remains a research tool at the present time, it is our contention that this technology will figure prominently in risk assessment strategies in the future.
Article
A progressive chain of pathophysiological events links cardiovascular risk factors to clinical manifestations of disease and life-threatening cardiovascular events. This chain--the cardiovascular continuum--underlies cardiovascular disease and holds the key to its prevention and treatment. Progressive tissue damage can result in morbidity from congestive heart failure, end-stage heart disease, nephrotic proteinuria and dementia and, eventually, death from cardio- or cerebrovascular causes. The renin-angiotensin-aldosterone system (RAAS) is involved at all stages of the cardiovascular continuum, because the effector molecules of the RAAS, angiotensin II in particular, have direct pathobiological effects on a variety of tissues, including the endothelium, vascular smooth muscle and the renal mesangium. Clinical trials of angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors have demonstrated the essential validity of this hypothesis. Interruption of the RAAS has been shown to reduce cardiovascular morbidity and mortality in patients with left ventricular hypertrophy, heart failure and post-myocardial infarction, as well as renal disease in patients with type 2 diabetes. Key questions remain, however. What are the clinical effects of combination ARB and ACE inhibitor treatment? How will combinations of RAAS blockade with other agents, such as statins, affect the cardiovascular continuum? Answers to these questions will require well-planned, adequately powered clinical trials, such as the Programme of Research tO evaluate Telmisartan End-organ proteCTION (PROTECTION) and the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) programmes. However, it is already clear that RAAS blockade is an essential part of blocking progression along the cardiovascular continuum.
Article
The application of fluid shear stress to endothelial cells elicits the formation of nitric oxide (NO) and phosphorylation of the endothelial NO synthase (eNOS). Shear stress also elicits the enhanced tyrosine phosphorylation of endothelial proteins, especially of those situated in the vicinity of cell-cell contacts. Since a major constituent of these endothelial cell-cell contacts is the platelet endothelial cell adhesion molecule-1 (PECAM-1) we assessed the role of PECAM-1 in the activation of eNOS. In human endothelial cells, shear stress induced the tyrosine phosphorylation of PECAM-1 and enhanced the association of PECAM-1 with eNOS. Endothelial cell stimulation with shear stress elicited the phosphorylation of Akt and eNOS as well as of the AMP-activated protein kinase (AMPK). While the shear-stress-induced tyrosine phosphorylation of PECAM-1 as well as the serine phosphorylation of Akt and eNOS were abolished by the pre-treatment of cells with the tyrosine kinase inhibitor PP1 the phosphorylation of AMPK was unaffected. Down-regulation of PECAM-1 using a siRNA approach attenuated the shear-stress-induced phosphorylation of Akt and eNOS, as well as the shear-stress-induced accumulation of cyclic GMP levels while the shear-stress-induced phosphorylation of AMPK remained intact. A comparable attenuation of Akt and eNOS (but not AMPK) phosphorylation and NO production was also observed in endothelial cells generated from PECAM-1-deficient mice. These data indicate that the shear-stress-induced activation of Akt and eNOS in endothelial cells is modulated by the tyrosine phosphorylation of PECAM-1 whereas the shear-stress-induced phosphorylation of AMPK is controlled by an alternative signaling pathway.
Article
The renin-angiotensin system (RAS) is critically involved in cardiovascular and renal function and in disease conditions, and has been shown to be a far more complex system than initially thought. A recently discovered homologue of angiotensin-converting enzyme (ACE)--ACE2--appears to negatively regulate the RAS. ACE2 cleaves Ang I and Ang II into the inactive Ang 1-9 and Ang 1-7, respectively. ACE2 is highly expressed in kidney and heart and is especially confined to the endothelium. With quantitative trait locus (QTL) mapping, ACE2 was defined as a QTL on the X chromosome in rat models of hypertension. In these animal models, kidney ACE2 messenger RNA and protein expression were markedly reduced, making ACE2 a candidate gene for this QTL. Targeted disruption of ACE2 in mice failed to elicit hypertension, but resulted in severe impairment in myocardial contractility with increased angiotensin II levels. Genetic ablation of ACE in the ACE2 null mice rescued the cardiac phenotype. These genetic data show that ACE2 is an essential regulator of heart function in vivo. Basal renal morphology and function were not altered by the inactivation of ACE2. The novel role of ACE2 in hydrolyzing several other peptides-such as the apelin peptides, opioids, and kinin metabolites-raises the possibility that peptide systems other than angiotensin and its derivatives also may have an important role in regulating cardiovascular and renal function.
Article
The renin-angiotensin system (RAS) has been recognized for many years as critical pathway for blood pressure control and kidney functions. Although most of the well-known cardiovascular and renal effects of RAS are attributed to angiotensin-converting enzyme (ACE), much less is known about the function of ACE2. Experiments using genetically modified mice and inhibitor studies have shown that ACE2 counterbalances the functions of ACE and that the balance between these two proteases determines local and systemic levels of RAS peptides such as angiotensin II and angiotensin1-7. Ace2 mutant mice exhibit progressive impairment of heart contractility at advanced ages, a phenotype that can be reverted by loss of ACE, suggesting that these enzymes directly control heart function. Moreover, ACE2 is also found to be upregulated in failing hearts. In the kidney, ACE2 protein levels are significantly decreased in hypertensive rats, suggesting a negative regulatory role of ACE2 in blood pressure control. Moreover, ACE2 expression is downregulated in the kidneys of diabetic and pregnant rats and ACE2 mutant mice develop late onset glomerulonephritis resembling diabetic nephropathy. Importantly, ACE2 not only controls angiotensin II levels but functions as a protease on additional molecular targets that could contribute to the observed in vivo phenotypes of ACE2 mutant mice. Thus, ACE2 seems to be a molecule that has protective roles in heart and kidney. The development of drugs that could activate ACE2 function would allow extending our treatment options in diabetic nephropathy, heart failure, or hypertension.
Article
Angiotensin-converting enzyme-2 (ACE2), a membrane-bound carboxymonopeptidase highly expressed in the kidney, functions as a negative regulator of the renin-angiotensin system. Here we report early accumulation of fibrillar collagen in the glomerular mesangium of male ACE2 mutant (ACE2-/y) mice followed by development of glomerulosclerosis by 12 months of age whereas female ACE2 mutant (ACE2-/-) mice were relatively protected. Progressive kidney injury was associated with increased deposition of collagen I, collagen III and fibronectin in the glomeruli and increased urinary albumin excretion compared to age-matched control mice. These structural and functional changes in the glomeruli of male ACE2 mutant mice were prevented by treatment with the angiotensin II type-1 receptor antagonist irbesartan. Loss of ACE2 was associated with a marked increase in renal lipid peroxidation product formation and activation of mitogen-activated protein kinase and extracellular signal-regulated kinases 1 and 2 in glomeruli, events that are also prevented by angiotensin II type-1 receptor blockade. We conclude that deletion of the ACE2 gene leads to the development of angiotensin II-dependent glomerular injury in male mice. These findings have important implications for our understanding of ACE2, the renin-angiotensin system, and gender in renal injury, with ACE2 likely to be an important therapeutic target in kidney disease.
Article
The endothelium is critically involved in modulating vascular tone through the release of vasodilator (mainly nitric oxide; NO) and vasoconstrictor agents. Under normal conditions the endothelium induces NO-mediated vasodilation, and opposes cell adhesion and thrombosis. Angiotensin II-induced generation of reactive oxygen species plays a key role in the pathophysiology of endothelial dysfunction by reducing NO bioavailability. Endothelial dysfunction is associated with several pathologic conditions, including hypertension and diabetes, and is characterized by altered vascular tone, inflammation, and thrombosis in the vascular wall. Inhibition of the renin-angiotensin-aldosterone system has induced beneficial effects on endothelial function in animals and humans. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists have improved endothelial function in hypertension and diabetes, slowed the progression of atherosclerosis, and reduced the risk associated with cardiovascular disease.
Article
The formation of angiotensin-(1-7) from either angiotensin (Ang) I or Ang II in failing human hearts is not well understood. Angiotensinase activity in left and right ventricular membranes from 14 idiopathic dilated cardiomyopathy (IDC), 8 primary pulmonary hypertension (PPH), and 13 nonfailing human hearts was measured with either 125I-Ang I or 125I-Ang II as substrate. Ang-(1-7)-forming activity from 125I-Ang I was inhibited by thiorphan. With 125I-Ang II as substrate, Ang-(1-7) formation was inhibited by the ACE2-specific inhibitor C16. Western blotting with an anti-ACE2 antibody confirmed the presence of ACE2. Angiotensinase activity with 125I-Ang I as substrate was increased in failing IDC left ventricles (LVs) compared with nonfailing LVs (P<0.001). Ang-(1-7)-forming activity with 125I-Ang II as substrate was increased in both failing LVs and right ventricles (RVs) of IDC hearts and only in failing RVs of PPH hearts (PPH LV, 51.12+/-5.25; PPH RV, 89.97+/-11.21; IDC LV, 139.7+/-21.96; and IDC RV, 192.7+/-5.43; NF LV, 32.89+/-5.38; NF RV 40.49+/-10.66 fmol/min per milligram (P<0.05 PPH RV versus PPH LV; P<0.05 PPH RV versus NF RV; P<0.001 IDC LV versus NF LV; P<0.001 IDC RV versus NF RV). Ang-(1-7)-forming activity from both Ang I and Ang II was increased in failing human heart ventricles but was mediated by at least two different angiotensinases. The first, which demonstrated substrate preference for Ang I, was neutral endopeptidase (NEP)-like. The second was ACE2, as demonstrated by Western blotting and inhibition of activity with C16.
Article
Therapeutic modulation of the renin-angiotensin system is not complete without taking into consideration the beneficial effects of angiotensin-(1-7) in cardiovascular pathology. Various pharmacological pathways are already exploited to involve this heptapeptide in therapy as both inhibitors of angiotensin-converting enzyme and angiotensin II type 1 receptor blockers increase its levels. These drugs and administered angiotensin-(1-7) elicit various common effects, and some effects of the drugs are partially mediated by angiotensin-(1-7). The pharmacodynamic profile of angiotensin-(1-7) is rather complex, and in vitro and in vivo studies demonstrated a wide palette of effects for angiotensin-(1-7), some of them potentially beneficial for cardiovascular disease. Using various animal models to study cardiovascular physiology and disease it was shown that angiotensin-(1-7) has antihypertensive, antihypertrophic, antifibrotic and antithrombotic properties, all properties that may prove beneficial in a clinical setting. We also observed a novel action of angiotensin-(1-7), namely its capacity to stimulate the proliferation of endothelial progenitor cells. Access of angiotensin-(1-7) to the clinic, however, is restricted due to its unfavorable pharmacokinetic properties. In order to benefit of the therapeutic potential of angiotensin-(1-7) it is crucial to increase its half-life, either by using more stable analogues, which are now under development, or specific delivery methods. We here review the pharmacological characteristics and therapeutic potential of angiotensin-(1-7), implementing the experimental strategies taken to exploit the pharmacological mechanism of this heptapeptide in a clinical setting, and present our contribution to this field of research.