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Angiotensin converting enzyme-2 confers endothelial protection and attenuates atherosclerosis
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.
... The effects of ACE2 on the neovascularization capacity have also been studied in vivo and in vitro. Experimental findings indicate that overexpression of ACE2 promotes endothelial cell migration and results in the formation of new capillaries in the tissues [7]. Therefore, it can be inferred that ACE2 operates within the endothelium to modulate Ang II levels by facilitating its breakdown and augmenting the generation of Ang (1-7), a molecule endowed with vascular-protective properties. ...
... Therefore, it can be inferred that ACE2 operates within the endothelium to modulate Ang II levels by facilitating its breakdown and augmenting the generation of Ang (1-7), a molecule endowed with vascular-protective properties. Improvement of endothelial function is the likely mechanism through which ACE2 exerts its cardio-vascular protective effect [7]. It was found that Ang (1-7) increases the vascular reparative function of CD34+ cells isolated from mice with diabetes [49]. ...
Background: Cardiac aging is associated with myocardial remodeling and reduced angiogenesis. Counteracting these changes with natural products is a preventive strategy with great potential. The aim of this study was to evaluate the effect of Aronia melanocarpa fruit juice (AMJ) supplementation on age-related myocardial remodeling in aged rat hearts. Methods: Healthy male Wistar rats (n = 24) were divided into three groups: (1) young controls (CY)—age 2 months; (2) old controls (CO)—age 27 months; (3) AMJ group—27-month-old animals, supplemented with Aronia melanocarpa juice (AMJ) at a dose of 10 mL∙kg⁻¹ for 105 days. After this period, the hearts of the animals were fixed, embedded in paraffin, and immunohistochemical and morphometric analyses were performed. Results: A higher vascular and capillary density was found in the hearts of the AMJ group, as compared to CO. The mean number of CD34+ cells in the myocardium increased by 18.6% in the AMJ group, as compared to CO (p < 0.05). Furthermore, the angiotensin converting enzyme 2 (ACE2) immunoexpression in the myocardium increased by 37% (p < 0.05) and the Proto-oncogene Mas receptor (MAS1) immunoexpression increased by 6% (p < 0.05) in the AMJ group, as compared to CO. Conclusions: As a result of the application of AMJ, noticeable neovascularization was found, which indicates improved myocardial nourishment. The present study demonstrates for the first time that polyphenol-rich AMJ can positively influence age-related microvascular myocardial remodeling in rats, thus outlining its potential as a preventive agent for healthy cardiac aging.
... Similarly, in HFD-fed Ldlr -/mice, ACE2 deletion in macrophages significantly increased atherosclerotic plaque and promoted the release of inflammatory cytokines and the adhesion of monocytes to ECs [45] . On the contrary, overexpression of ACE2 in monocytes or ECs leads to reduced endothelial adhesion and migration and the expression of adhesion factors [46,47] . Recombinant adenovirus-mediated ACE2 overexpression ACE2 significantly reduced atherosclerotic plaques in HFD-fed ApoE -/mice [47] and enhanced atherosclerotic plaque stability in New Zealand rabbits by improving endothelial function, inhibiting inflammatory response and monocyte adhesion, reducing macrophage infiltration, and is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint ...
... On the contrary, overexpression of ACE2 in monocytes or ECs leads to reduced endothelial adhesion and migration and the expression of adhesion factors [46,47] . Recombinant adenovirus-mediated ACE2 overexpression ACE2 significantly reduced atherosclerotic plaques in HFD-fed ApoE -/mice [47] and enhanced atherosclerotic plaque stability in New Zealand rabbits by improving endothelial function, inhibiting inflammatory response and monocyte adhesion, reducing macrophage infiltration, and is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint ...
Atherosclerosis (AS) is a progressive arterial disease characterized by chronic inflammation and plaque formation in blood vessel walls. ELABELA, an endogenous ligand for the G protein-coupled receptor APJ (apelin peptide jejunum, apelin receptor), has multiple pharmacological activities for protecting the cardiovascular system. This study aimed to determine the potential anti-atherosclerotic effect of ELABELA and reveal the underlying mechanisms. Plasma ELABELA levels were significantly reduced and negatively correlated with plasma MMP2 and MMP9 levels in AS patients and high-fat diet-induced atherosclerotic ApoE−/− mice. Plasma ELABELA levels exhibited a potential diagnostic value for AS patients. Application of ELABELA-21 (ELA-21) significantly decreased atherosclerotic plaque area and inflammation in the aortas from the ApoE−/− mice. ELA-21 administration modulated the balance between M1 and M2 macrophages in the abdominal cavity and aorta roots toward a more anti-inflammatory status, accompanied by reduced MMP2, MMP9, and PRR and enhanced APJ, ACE, and ACE2 protein expression in plaques within aortic roots and decreased plasma sPRR levels. In vitro, ELA-21 effectively suppressed oxidized-low-density lipoprotein-induced foam cell formation and LPS/IFN-γ-induced M1 polarization in THP-1 cells. Interestingly, the anti-inflammatory effect of ELA-21 was further enhanced by APJ inhibitor ML221, accompanied by elevated ACE and ATP6AP2 and reduced ACE2 mRNA levels. Collectively, our data highlighted the diagnostic and therapeutic potential of ELABELA on AS. ELA-21 protects against AS by inhibiting atherosclerotic plaque formation and promoting a more stable plaque phenotype, possibly via restoring the M1/M2 macrophage balance, enhancing macrophage ACE and ACE2 expression, and inhibiting the PRR system. ELABELA may be a novel biomarker and candidate therapeutic target for treating AS.
... In uninfected cells, the main product of ACE2, Ang 1-7, binds to Mas receptors within the cardiovascular system and induces essential protective effects through its anti-inflammatory, antiproliferative-antifibrotic and antioxidant actions [2,3]. However, dysfunction of the ACE2/Ang1-7/Ang1-9/Mas receptor pathway in the vasculature was shown to promote heart and vessel inflammation, structural rebuilding of the vasculature and endothelium-dependent or endothelium-independent dysfunction, including accelerated thrombogenesis [4,5]. Thus, we could assume that the dysfunction of ACE2-mediated mechanisms could be detrimental, especially in individuals with preexisting cardiovascular complications. ...
... The equilibrium concentration of angiotensin (1-10) (Ang I), angiotensin (1-8) (Ang II), angiotensin (1-7), and angiotensin (1)(2)(3)(4)(5) were identified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in heparinized plasma samples as described previously [26]. ...
Background:
Angiotensin converting enzyme 2 (ACE2) plays a crucial role in the infection cycle of SARS-CoV-2 responsible for formation of COVID-19 pandemic. In the cardiovascular system, the virus enters the cells by binding to the transmembrane form of ACE2 causing detrimental effects especially in individuals with developed hypertension or heart disease. Zofenopril, a H2S-releasing angiotensin-converting enzyme inhibitor (ACEI), has been shown to be effective in the treatment of patients with essential hypertension; however, in conditions of ACE2 inhibition its potential beneficial effect has not been investigated yet. Therefore, the aim of the study was to determine the effect of zofenopril on the cardiovascular system of spontaneously hypertensive rats, an animal model of human essential hypertension and heart failure, under conditions of ACE2 inhibition induced by the administration of the specific inhibitor MLN-4760 (MLN).
Results:
Zofenopril reduced MLN-increased visceral fat to body weight ratio although no changes in systolic blood pressure were recorded. Zofenopril administration resulted in a favorable increase in left ventricle ejection fraction and improvement of diastolic function regardless of ACE2 inhibition, which was associated with increased H2S levels in plasma and heart tissue. Similarly, the acute hypotensive responses induced by acetylcholine, L-NAME (NOsynthase inhibitor) and captopril (ACEI) were comparable after zofenopril administration independently from ACE2 inhibition. Although simultaneous treatment with zofenopril and MLN led to increased thoracic aorta vasorelaxation, zofenopril increased the NO component equally regardless of MLN treatment, which was associated with increased NO-synthase activity in aorta and left ventricle. Moreover, unlike in control rats, the endogenous H2S participated in maintaining of aortic endothelial function in MLN-treated rats and the treatment with zofenopril had no impact on this effect.
Conclusions:
Zofenopril treatment reduced MLN-induced adiposity and improved cardiac function regardless of ACE2 inhibition. Although the concomitant MLN and zofenopril treatment increased thoracic aorta vasorelaxation capacity, zofenopril increased the participation of H2S and NO in the maintenance of endothelial function independently from ACE2 inhibition. Our results confirmed that the beneficial effects of zofenopril were not affected by ACE2 inhibition, moreover, we assume that ACE2 inhibition itself can lead to the activation of cardiovascular compensatory mechanisms associated with Mas receptor, nitrous and sulfide signaling.
... ACE2 was first discovered in 2000 by Tipnis and Donoghue [31,32]. Experiments performed in ACE2 knockout mice models underline the importance of this enzyme in diabetes [33], cardiac function, hypoxia, cell contractility [34][35][36], endothelial function [37], liver [38], and kidney injury [39,40]. Its overexpression is associated with improved pressure and glycemic control, reduced oxidative stress and modulation of ER stress [41], prevention of cardiac hypertrophy and fibrosis induced by Ang II [42], and of acute lung injury by the modulation of pro-inflammatory molecules [43], while its loss leads to cardiac dysfunction, hypertrophy, fibrosis and a greater diastolic function [44]. ...
... According to what has been said so far, it seems clear that the ACE2/Ang 1-7/MasR axis plays an important role in cardiovascular prevention and protection from organ remodeling. Indeed, several studies reported the key role of ACE2 in diabetes [33], hepatic [38], lung inflammation [43], cardiac and renal function, vascular contractility, and endothelial function [34][35][36][37]39,40]. Also, Ang 1-7 plays a protective role in diabetes, vascular prevention, coagulation cascade, cardiac and renal damage [41,54] and pulmonary fibrosis [53]. ...
In the last two decades, the study of the renin–angiotensin–aldosterone system (RAAS) has revealed a counterregulatory protective axis. This protective arm is characterized by ACE2/Ang 1-7/MasR and Ang 1-9 that largely counteracts the classic arm of the RAAS mediated by ACE/Ang II/AT1R/aldosterone and plays an important role in the prevention of inflammation, oxidative stress, hypertension, and cardiovascular remodeling. A growing body of evidence suggests that enhancement of this counterregulatory arm of RAAS represents an important therapeutic approach to facing cardiovascular comorbidities. In this review, we provide an overview of the beneficial effects of ACE2, Ang 1-7/MasR, and Ang 1-9 in the context of oxidative stress, vascular dysfunction, and organ damage.
... Angiotensin-converting enzyme 2 (ACE2) is widely distributed in the endothelium [5]. ACE2 is an essential regulator of the renin-angiotensin system (RAS) and plays an essential role in maintaining endothelial integrity [6]. SARS-CoV-2 binds to the endothelial ACE2 receptor and produces an imbalance of RAS that is key to understanding the perfusion abnormalities (PA) that occur in COVID-19 pneumonia [7,8]. ...
... Both angiotensin I (Ang I) and angiotensin II (Ang II) accumulate due to viral blockade and down-regulation [5]. Angiotensin-converting enzyme (ACE) is not engaged by the virus, and the conversion of Ang I to Ang II continues unabated eventually leading to unopposed accumulation of Ang II [5,6]. Ang II produces vasoconstriction and endothelial dysfunction with less production of nitric oxide in early phases of disease, leading to a progressive V/Q mismatch with extensive areas of apparently healthy but hypoperfused lung that function as alveolar dead space [6,8, 65-year-old female patient, 10 days since symptom onset. ...
Purpose:
To evaluate whether a subtraction CT angiography (sCTA) perfusion score may have prognostic value in patients with COVID-19 pneumonia.
Method:
This prospective cohort study included adult patients with RT-PCR-confirmed SARS-CoV-2 infection admitted to the ED and a sCTA performed within 24 h of admission between June and September 2020. Perfusion abnormalities (PA) in areas of apparently spared lung parenchyma on conventional CT images were assessed with sCTA perfusion score. Airspace disease extension was assessed with CT severity scores, which were then correlated with clinical outcomes (admission to ICU, requirement of IMV, and death). Inter-rater reliability (IRR) was assessed using Cohen's Kappa. Independent predictors of adverse outcomes were evaluated by multivariable logistic regression analyses using the Hosmer and Lemeshow's test.
Results:
191 patients were included: 112 males (58%), median age of 60.8 years (SD ± 16.0). The IRR was very high (median Kappa statistic: 0.95). No association was found between perfusion CT scores and D-dimer levels (Kendall's Tau-B coefficient = 0.08, p = 0.16) or between PaO2/FiO2 ratios and D-dimer levels (Kendall's Tau-B coefficient = -0.10, p = 0.07). Multivariate analyses adjusting for parenchymal disease extension, vascular beaded appearance, pulmonary embolism, sex, and age showed that severe PA remained a significant predictor for ICU admission (AOR: 6.25, 95% CI 2.10-18.7, p = 0.001). The overall diagnostic capacity of this model was adequate (ROC AUC: 0.83; 95% CI 0.77-0.89).
Conclusions:
The assessment of pulmonary perfusion abnormalities in areas of apparently spared lung parenchyma on conventional CT images via sCTA perfusion scoring has prognostic value in COVID-19 pneumonia.
... 50 ACE2 is a negative regulator of RAS, and through catalytic cleavage of angiotensin I and II to angiotensin-(1-7) has vasodilatory, antiproliferative, antiangiogenic, and anti-inflammatory properties. 51,52 The COVID-19 Phase 2 clinical trial (NCT04335136) demonstrated that treatment with APN01 was safe and that patients showed improvement on several clinical parameters, but it failed to meet clinical endpoints. 49,53 We speculate that this could have at least in part been due to the relatively low affinity of monomeric ACE2 for spike protein (15-44 nM) 35,40,41 and the intravenous (IV) route for administration used in the trial. ...
... 54 Despite these high doses, the resulting amount of mAb that reaches the lungs is still low compared to circulation and suboptimal as a therapeutic dose. [49][50][51][52] As the respiratory tract is the major target and site of viral replication for SARS-CoV-2, 55 an alternative strategy to modulating progression of COVID-19 may be through early administration by IN delivery to confer protection against respiratory infection. IN administration can be used to non-invasively deliver higher concentrations of antibody therapeutic directly to the airway tissues and better target the site of virus replication in the respiratory tract. ...
As immunological selection for escape mutants continues to give rise to future SARS-CoV-2 variants, novel universal therapeutic strategies against ACE2-dependent viruses are needed. Here we present an IgM-based decavalent ACE2 decoy that has variant-agnostic efficacy. In immuno-, pseudovirus, and live virus assays, IgM ACE2 decoy had potency comparable or superior to leading SARS-CoV-2 IgG-based mAb therapeutics evaluated in the clinic, which were variant-sensitive in their potency. We found that increased ACE2 valency translated into increased apparent affinity for spike protein and superior potency in biological assays when decavalent IgM ACE2 was compared to tetravalent, bivalent, and monovalent ACE2 decoys. Furthermore, a single intranasal dose of IgM ACE2 decoy at 1 mg/kg conferred therapeutic benefit against SARS-CoV-2 Delta variant infection in a hamster model. Taken together, this engineered IgM ACE2 decoy represents a SARS-CoV-2 variant-agnostic therapeutic that leverages avidity to drive enhanced target binding, viral neutralization, and in vivo respiratory protection against SARS-CoV-2.
... Limitar su generación es otro de los beneficios del uso de IECA, aunque también potenciar su degradación ha sido blanco de estudio. La enzima convertidora de angiotensina 2 (ACE2) es la responsable de degradar ANG2 a angiotensina-(1-7), molécula que actúa como antinflamatorio y vasodilatador, por lo que potenciar ANG2 es otra estrategia en estudio (38) . ...
... ACE2 se encuentra altamente expresada en pulmón, corazón, riñones, páncreas y otros tejidos (40) . Como mencionamos anteriormente, a nivel vascular, ACE2 es altamente activa, degradando ANG2 y manteniendo un estado vasodilatador (38) . Es por esto que además de ser una enfermedad que se presenta principalmente por síntomas respiratorios, se considera también como una enfermedad vascular. ...
Endothelium is the inner layer of vessels that separates circulating blood from the rest of the body tissues. Since its discovery, it has been involved in various functions, both systemic and organ specific. Currently, endothelial damage and failure in its functions is considered a key element in pathophysiology of various clinical scenarios, among which we may find COVID-19. Hence, it has been a target in development of strategies that seek to maintain, enhance or repair its function. The purpose of the following review is to describe what an endothelial function is about, its relation with current medical practice, and its implications in the SARSCoV-2 pandemic.
... ACE2mediated hydrolysis of Ang II to Ang-(1-7) and the activation of the ACE2/Ang II/Mas receptor axis antagonise the detrimental effects of ACE/Ang II/AT 1 receptor axis, with beneficial outcomes on cardiovascular physiology and homeostasis [36,43]. Specifically, the ACE2/Ang II/Mas receptor axis-mediated cardioprotective effects include maintenance of endothelial function, suppression of reactive oxygen species (ROS) generation, enhanced atherosclerotic plaque stability, vasodilation, reduced salt and water retention, as well as inhibition of profibrotic and prohypertrophic mechanisms [44][45][46][47] (Figure 1). taglomerular apparatus [39,40]. ...
... ACE2-mediated hydrolysis of Ang II to Ang-(1-7) and the activation of the ACE2/Ang II/Mas receptor axis antagonise the detrimental effects of ACE/Ang II/AT1 receptor axis, with beneficial outcomes on cardiovascular physiology and homeostasis [36,43]. Specifically, the ACE2/Ang II/Mas receptor axis-mediated cardioprotective effects include maintenance of endothelial function, suppression of reactive oxygen species (ROS) generation, enhanced atherosclerotic plaque stability, vasodilation, reduced salt and water retention, as well as inhibition of profibrotic and prohypertrophic mechanisms [44][45][46][47] (Figure 1). ...
The clinical manifestations of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection responsible for coronavirus disease 2019 (COVID-19) commonly include dyspnoea and fatigue, and they primarily involve the lungs. However, extra-pulmonary organ dysfunctions, particularly affecting the cardiovascular system, have also been observed following COVID-19 infection. In this context, several cardiac complications have been reported, including hypertension, thromboembolism, arrythmia and heart failure, with myocardial injury and myocarditis being the most frequent. These secondary myocardial inflammatory responses appear to be associated with a poorer disease course and increased mortality in patients with severe COVID-19. In addition, numerous episodes of myocarditis have been reported as a complication of COVID-19 mRNA vaccinations, especially in young adult males. Changes in the cell surface expression of angiotensin-converting enzyme 2 (ACE2) and direct injury to cardiomyocytes resulting from exaggerated immune responses to COVID-19 are just some of the mechanisms that may explain the pathogenesis of COVID-19-induced myocarditis. Here, we review the pathophysiological mechanisms underlying myocarditis associated with COVID-19 infection, with a particular focus on the involvement of ACE2 and Toll-like receptors (TLRs).
... These components are thought to have protective effects on CVDs, although the exact mechanisms underlying such effects are not completely understood [5]. In rodent models, ACE2, through catabolism of AngII [6][7][8] and Ang-(1-7) [9][10][11][12], showed beneficial effects on blood pressure (BP), atherosclerosis, cardiac remodeling, and heart failure. A few animal model studies suggested that ACE inhibitor or AngII receptor blocker (ARB) treatments can cause ACE2 upregulation with consequential beneficial effects on CVDs [13]. ...
... In that study, olmesartan was an independent predictor of urinary ACE2 levels, with potential additional renoprotective effects [15]. However, the study was an observational study with a small sample size, and it did not measure the plasma levels of ACE2 or Ang- (1)(2)(3)(4)(5)(6)(7). ...
Background
Recent studies suggest that angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1–7) [Ang-(1–7)] might have beneficial effects on the cardiovascular system. We investigated the effects of olmesartan on the changes in serum ACE2 and Ang-(1–7) levels as well as kidney and vascular function in patients with type 2 diabetes and hypertension.
Methods
This was a prospective, randomized, active comparator-controlled trial. Eighty participants with type 2 diabetes and hypertension were randomized to receive 20 mg of olmesartan (N = 40) or 5 mg of amlodipine (N = 40) once daily. The primary endpoint was changes of serum Ang-(1–7) from baseline to week 24.
Results
Both olmesartan and amlodipine treatment for 24 weeks decreased systolic and diastolic blood pressures significantly by > 18 mmHg and > 8 mmHg, respectively. Serum Ang-(1–7) levels were more significantly increased by olmesartan treatment (25.8 ± 34.5 pg/mL → 46.2 ± 59.4 pg/mL) than by amlodipine treatment (29.2 ± 38.9 pg/mL → 31.7 ± 26.0 pg/mL), resulting in significant between-group differences (P = 0.01). Serum ACE2 levels showed a similar pattern (6.31 ± 0.42 ng/mL → 6.74 ± 0.39 ng/mL by olmesartan treatment vs. 6.43 ± 0.23 ng/mL → 6.61 ± 0.42 ng/mL by amlodipine treatment; P < 0.05). The reduction in albuminuria was significantly associated with the increases in ACE2 and Ang-(1–7) levels (r = − 0.252 and r = − 0.299, respectively). The change in Ang-(1–7) levels was positively associated with improved microvascular function (r = 0.241, P < 0.05). Multivariate regression analyses showed that increases in serum Ang-(1–7) levels were an independent predictor of a reduction in albuminuria.
Conclusions
These findings suggest that the beneficial effects of olmesartan on albuminuria may be mediated by increased ACE2 and Ang-(1–7) levels. These novel biomarkers may be therapeutic targets for the prevention and treatment of diabetic kidney disease.
Trial registration: ClinicalTrials.gov NCT05189015.
... Moreover, an in-vitro study revealed that angiogenesis can be promoted by angiotensin 1-7 via increased formation of vascular endothelial growth factor D (VEGF-D) and matrix metalloproteinase-9 (MMP-9) [63]. Angiotensin 1-7 also plays a role in reducing atherosclerotic lesion burden, acts as a plaque stabilization, and has anti-thrombotic properties [64][65][66]. In a similar fashion to angiotensin 1-7, angiotensin 1-9 can prevent myocardial hypertrophy, attenuate the myocardial cell fibrotic process, and promote vasodilatation via the AT2R signaling pathway [67,68]. ...
... Furthermore, angiotensin II can activate platelets and disrupt the anticoagulant process [46][47][48]. Simultaneously, lower levels of angiotensin 1-7 and angiotensin 1-9 lowered their anti-thrombotic, plaque stabilization, and vasodilatory activities [64][65][66][67]. These mechanisms, when combined, might aggravate the underlying atherosclerotic lesions in the coronary artery. ...
Long COVID or post-acute Coronavirus disease 2019 (COVID-19), a malady defined by the persistence of COVID-19 symptoms for weeks or even months, is expected to affect the lives of millions of individuals worldwide significantly. Cardiopulmonary symptoms such as chest discomfort, shortness of breath, fatigue, and autonomic manifestations such as postural orthostatic tachycardia syndrome, and arrhythmias are prevalent and widely recognized. A variety of cardiovascular problems, including myocardial inflammation, myocardial infarction, ventricular dysfunction, and endothelial dysfunction, have been described in individuals following the initial acute phase. With over 10,000 published publications on COVID-19 and the cardiovascular system, presenting an unbiased thorough analysis of how SARS-CoV-2 affects the system is essentially challenging. This review will provide an overview of frequent cardiovascular manifestations, emphasizing consequences, proposed pathophysiology, and clinical diagnostic manifestation strategy.
... Nicotinamide adenine dinucleotide phosphate (NADPH) inhibition leads to reduced oxidative stress by inhibiting the detrimental activity of inducible nitric oxide (NO) synthase [37]. ACE2 knockout display hypertensive phenotypes aggravated by endothelial dysfunction, proved by the worse outcome induced by diabetes-and shock-induced kidney injury, viral lung injury, and chronic liver injury [38]. The unifying characteristic among these models is an increase in oxidative stress in ACE2 knockout male mice [39,40]. ...
... Figure 4 sums up the most important paths Ang (1-7) acts. kidney injury, viral lung injury, and chronic liver injury [38]. The unifying characte among these models is an increase in oxidative stress in ACE2 knockout male mice [3 Arterial Blood Pressure Vascular smooth muscle tone may be modulated either directly-as determine upregulation of endothelial and neuronal NO synthase, subsequent cyclic GMP rise vasodilation-or indirectly. ...
The COVID-19 pandemic has put a tremendous stress on the medical community over the last two years. Managing the infection proved a lot more difficult after several research communities started to recognize the long-term effects of this disease. The cellular receptor for the virus was identified as angiotensin-converting enzyme-2 (ACE2), a molecule responsible for a wide array of processes, broadly variable amongst different organs. Angiotensin (Ang) 1-7 is the product of Ang II, a decaying reaction catalysed by ACE2. The effects observed after altering the level of ACE2 are essentially related to the variation of Ang 1-7. The renin-angiotensin-aldosterone system (RAAS) is comprised of two main branches, with ACE2 representing a crucial component of the protective part of the complex. The ACE2/Ang (1-7) axis is well represented in the testis, heart, brain, kidney, and intestine. Infection with the novel SARS-CoV-2 virus determines downregulation of ACE2 and interrupts the equilibrium between ACE and ACE2 in these organs. In this review, we highlight the link between the local effects of RAAS and the consequences of COVID-19 infection as they arise from observational studies.
... Following 48-hour incubation, TLL1 activity in the extracellular culture medium was measured as previously described (13). In brief, extracellular culture media were . ...
Background
Mitral valve prolapse (MVP) is a common cardiac valvular anomaly that can be caused by mutations in genes of various biological pathways. Individuals of three generations of a kindred presented with apparently dominant heredity of isolated MVP.
Methods
Clinical evaluation and echocardiography for all complying family members (n=13). Whole exome and genome sequencing data of two affected individuals were analyzed, delineating shared heterozygous variants, further tested for segregation within the
kindred (Sanger sequencing). Tolloid Like 1 (TLL1) enzymatic activity was assayed in media of HEK293 cells transfected with wild-type versus mutant TLL1.
Results
The only heterozygous variant segregating in the affected kindred as expected for dominant heredity of MVP was p.T253A, within the catalytic domain of TLL1. Of eight heterozygotes, six had MVP and two had trivial mitral regurgitation. Activity assay in extra-cellular media of HEK293-transfected cells showed that over time (12 hours), the enzymatic activity of the mutated TLL1 protein was X3.4 higher than that of the wild type.
Conclusions
Our genetic and biochemical studies show that a TLL1 Gain-of-Function mutation, prolonging the half-life of TLL1 active protein in the extracellular matrix (ECM), causes autosomal dominant MVP with variable expressivity. TLL1 encodes an extracellular metalloprotease regulating ECM composition and maintenance.
Heterozygous Loss-of-Function TLL1 mutations have been previously shown to cause autosomal dominant atrial septal defects. Our findings enable novel insights into molecular pathways of valvular physiology and disease, the role of TLL1 in human development, and the differing phenotypes of Loss-of-Function and Gain-of-Function mutations of the same gene.
... There are also studies demonstrating that overexpression of ACE2 or infusion of recombinant ACE2 can improve vascular dysfunction and atherosclerosis, but there are no studies on AAA. [97][98][99][100][101][102] This section highlights key studies on the correlation of ACE2/Ang-(1-7)/MasR with AAA ( Table 1). The discussion on the involvement of Ang-(1-7)/MasR in AAA formation will be continued in the following paragraphs. ...
Aortic aneurysm (AA) is an aortic disease with a high mortality rate, and other than surgery no effective preventive or therapeutic treatment have been developed. The renin–angiotensin system (RAS) is an important endocrine system that regulates vascular health. The ACE2/Ang‐(1–7)/MasR axis can antagonize the adverse effects of the activation of the ACE/Ang II/AT1R axis on vascular dysfunction, atherosclerosis, and the development of aneurysms, thus providing an important therapeutic target for the prevention and treatment of AA. However, products targeting the Ang‐(1–7)/MasR pathway still lack clinical validation. This review will outline the epidemiology of AA, including thoracic, abdominal, and thoracoabdominal AA, as well as current diagnostic and treatment strategies. Due to the highest incidence and most extensive research on abdominal AA (AAA), we will focus on AAA to explain the role of the RAS in its development, the protective function of Ang‐(1–7)/MasR, and the mechanisms involved. We will also describe the roles of agonists and antagonists, suggest improvements in engineering and drug delivery, and provide evidence for Ang‐(1–7)/MasR's clinical potential, discussing risks and solutions for clinical use. This study will enhance our understanding of AA and offer new possibilities and promising targets for therapeutic intervention.
... 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. ...
... ACE2 is also expressed by endothelial cells. 60,61 Notably, one-third of lung cells are endothelial cells. 62 Viral invasion may be facilitated by endothelium damage-induced microvascular permeability. ...
p>In December 2019, a novel coronavirus, now named as SARS-CoV-2, caused a series of acute atypical respiratory diseases in Wuhan, Hubei Province, China. The disease caused by this virus was termed COVID-19. The virus is transmittable between humans and has caused pandemic worldwide. The number of death tolls continues to rise and a large number of countries have been forced to do social distancing and lockdown. Lack of targeted therapy continues to be a problem. Epidemiological studies showed that elder patients were more susceptible to severe diseases, while children tend to have milder symptoms. Here we reviewed the current knowledge about this disease and considered the potential explanation of the different symptomatology between children and adults.</p
... Endothelial cells in both the heart and vasculature are targets of cardiovascular and systemic complications [64]. Some studies have suggested that ACE2 receptors are located within endothelial cells and potentiate infection in a direct manner, similar to myocytes [65][66][67][68][69][70][71]. Further research has also postulated that pericytes, the cells that surround endothelial cells, may be the actual mediators of disease because they also possess ACE2 receptors [72]. ...
The SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) virus and the resulting COVID-19 pandemic have had devastating and lasting impact on the global population. Although the main target of the disease is the respiratory tract, clinical outcomes, and research have also shown significant effects of infection on other organ systems. Of interest in this review is the effect of the virus on the cardiovascular system. Complications, including hyperinflammatory syndrome, myocarditis, and cardiac failure, have been documented in the context of COVID-19 infection. These complications ultimately contribute to worse patient outcomes, especially in patients with pre-existing conditions such as hypertension, diabetes, or cardiovascular disease (CVD). Importantly and interestingly, reports have demonstrated that COVID-19 also causes myocardial injury in adults without pre-existing conditions and contributes to systemic complications in pediatric populations, such as the development of multisystem inflammatory syndrome in children (MIS-C). Although there is still a debate over the exact mechanisms by which such complications arise, understanding the potential paths by which the virus can influence the cardiovascular system to create an inflammatory environment may clarify how SARS-CoV-2 interacts with human physiology. In addition to describing the mechanisms of disease propagation and patient presentation, this review discusses the diagnostic findings and treatment strategies and the evolution of management for patients presenting with cardiovascular complications, focusing on disease treatment and prevention.
... Снижение защиты приводит к накоплению супероксидов и как следствие запускается каскад ПОЛ [128]. Активация ПОЛ и ее циклично замкнутой системой самовоспроизведения приводит к стойкой дисфункции клеток в области поражения отягощая общее состояние пациентов [127][128][129][130]. ...
An analysis of data on a pressing issue — the COVID-19 pandemic was carried out. The intensity of infection in the population reached 285.5 cases per 10,000 population in the Kyrgyz Republic. The mortality rate for the entire pandemic period in the Kyrgyz Republic was 0.42 per 1,000 population. Therefore, the aspect of the region's climatic influence on the studied indicators is relevant given the high probability of the emergence of new types of human coronaviruses.
... Half of them had been previously identified as playing a role in mechanisms associated with atherosclerosis. Indeed, these proteins modulate a variety of biological functions such as vasoreactivity (ACE2, AHCY, CALCA, LEP, REN), [39][40][41][42][43] shear stress (PLXDC1), 44 42 , 43 , 51 , 60 The other half of the proteins had not previously been described as involved in atherosclerotic plaque formation, but a few have still been associated with coronary artery disease in clinical studies (BCAN, NID1, PRSS27, UMOD). 7 , 10 , 61 Although we followed the state-of-the-art workflow recommended by Nurmohamed et al. 19 for biomarker identification, we were unable to find an additive prognostic value of plasma proteins. ...
... Because this virus, like other viruses in its family, has a high tendency to enter the upper respiratory tract, and the lungs, with a wide network of blood vessels, are a good environment for the virus to multiply, and consequently, clinical manifestations begin with respiratory symptoms. And then, it appears in other organs (53,54). Since Kawasaki vasculitis is also a vascular endothelial disease that causes vascular complications by disrupting the regulatory mechanism of ACE2, it can be hypothesized that the causative agent of Kawasaki vasculitis may be the SARS-COV-2 virus (55). ...
Context: In 2019, a novel Coronavirus officially named by WHO as coronavirus disease of 2019 (COVID-19) pneumonia quickly spread worldwide and became a pandemic. At first, it was considered that the complications just included older populations, but its association with Kawasaki vasculitis disease further complicated the issues. Evidence Acquisition: A literature search was conducted using various scientific databases of Springer, Scopus, Wiley, Science Direct, PubMed, ProQuest, Cochrane Library, Embase, and Clinical Key. Keywords COVID-19, Kawasaki vasculitis, Mucocutaneous Lymph Node Syndrome, pediatric, RNA viruses, cytokine storm, 2019 nCoV Diseases, SARS CoV 2 Infection, and SARS CoV 2 were used to filter the search results. After assessing each retrieved article against inclusion-exclusion criteria, 63 papers were deemed eligible for inclusion in this review. Results: Our study linked Kawasaki disease with COVID-19 pneumonia in three pathways: (1) interference of angiotensin-converting enzyme 2 (ACE2) receptor and renin-angiotensin-aldosterone system (RAAS) in the pathogenesis of SARS CoV 2 and Kawasaki vasculitis diseases, (2) the similarity of clinical manifestation and immune system response in SARS CoV 2 and Kawasaki vasculitis diseases, (3) the role of COVID-19 as a risk factor next to other risk factors. Conclusions: Kawasaki vasculitis disease could be indicated along with infection with Coronaviridae viruses in pediatrics. Recognition of Kawasaki vasculitis disease with focusing on COVID-19 pathogenesis, aside from restriction of risk factors and detection of best treatment.
... It mainly acts as a mono-carboxypeptidase that preferably hydrolyzes between proline and a hydrophobic/ basic C-terminal amino acid. An enzymatic reaction, which is successfully catalyzed via ACE2, involves Ang1-8 degradation through the removal of its C-terminal phenylalanine for generating Ang1-7 [15][16][17] that is characterized by vasodilatory, antiproliferative, antiangiogenic, and antiinfammatory properties [18]. G protein-coupled Mas receptors mediate its efects [19]. ...
Due to the coronavirus disease 2019 (COVID-19), researchers all over the world have tried to find an appropriate therapeutic approach for the disease. The angiotensin-converting enzyme 2 (ACE2) has been shown as a necessary receptor to cell fusion, which is involved in infection due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is commonly crucial for all organs and systems. When ACE2 is downregulated via the SARS-CoV-2 spike protein, it results in the angiotensin II (Ang II)/angiotensin type 1 receptor axis overactivation. Ang II has harmful effects, which can be evidenced by dysfunctions in many organs experienced by COVID-19 patients. ACE2 is the SARS-CoV-2 receptor and has an extensive distribution; thus, some COVID-19 cases experience several symptoms and complications. We suggest strategy for the potential protective effect of ACE2 to the viral infection. The current review will provide data to develop new approaches for preventing and controlling the COVID-19 outbreak.
... 16 Conversely, ACE2 activation attenuated inflammation and improved Angiotensin II (Ang II) mediated vascular dysfunction. 17 The second attractive target for cardiovascular complications is the natriuretic peptide/particulate guanylyl cyclase A (pGCAR)/Cyclic guanosine monophosphate (cGMP) pathway. Natriuretic peptides are the hormones secreted by the heart, mainly involved in the homeostasis and function of the cardiovascular system. ...
Cardiovascular diseases (CVDs) are associated with vascular smooth muscle cell (VSMC) and endothelial cell (EC) damage. Angiotensin1-7 (Ang1-7) and B-type natriuretic peptide (BNP) are responsible for vasodilation and regulation of blood flow. These protective effects of BNP are primarily mediated by the activation of sGCs/cGMP/cGKI pathway. Conversely, Ang1-7 inhibits Angiotensin II-induced contraction and oxidative stress via Mas receptor activation. Thus, the aim of the study was to determine the effect of co-activation of MasR and particulate guanylate cyclase receptor (pGCA) pathways by synthesized novel peptide (NP) in oxidative stress-induced VSMCs and ECs. MTT and Griess reagent assay kits were used for the standardization of the oxidative stress (H2 O2 ) induced model in VSMCs. The expression of targeted receptors in VSMC was done by RT-PCR and Western blot analysis. Protective effect of NP in VSMC and EC was determined by immunocytochemistry, FACS analysis, and Western blot analysis. Underlying mechanisms of EC-dependent VSMC relaxation were done by determining downstream mRNA gene expression and intracellular calcium imaging of cells. Synthesized NP significantly improved oxidative stress-induced injury in VSMCs. Remarkably, the actions of NP were superior to that of the Ang1-7 and BNP alone. Further, a mechanistic study in VSMC and EC suggested the involvement of upstream mediators of calcium inhibition for the therapeutic effect. NP is reported to possess vascular protective activities and is also involved in the improvement of endothelial damage. Moreover, it is highly effective than that of individual peptides BNP and Ang1-7 and therefore it may represent a promising strategy for CVDs.
... Polymorphism of the ACE-2 D-allele was associated with higher risk of essential hypertension and higher ACE-2 plasma levels were indicative of patients at higher cardiovascular risk [48,68,69]. The role of ACE-2 in the cardiovascular system is somewhat controversial as it is known to stabilize atherosclerotic plaques and lower blood pressure through the conversion of Ang II (vasoconstrictor) into Ang-(1-7) [70][71][72]. ...
... To access host cells, SARS-CoV-2 uses a surface glycoprotein (peplomer) known as spike; ACE2 has been shown International Journal of Clinical Practice to be a coreceptor for coronavirus entry [40]. ACE2 is also expressed by endothelial cells [41], and other major clinical events usually observed in COVID-19 patients (e.g., high blood pressure [42], thrombosis [43] kidney disease [44], pulmonary embolism [45], cerebrovascular, and neurologic disorders) [46] indicate that the virus is targeting the endothelium, one of the largest organs in the human body [47]. In addition to this, evidence is emerging that the multiorgan injury observed in COVID-19 is a consequence of cytokineinduced endothelial dysfunction (endothelium) [48]. ...
Introduction:
COVID-19 pandemic has led to an increased rate of intensive care unit (ICU) stays. Intermediate care units (IMCUs) are a useful resource for the management of patients with severe COVID-19 that do not require ICU admission. In this research, we aimed to determine survival outcomes and parameters predicting mortality in patients who have been admitted to IMCU.
Materials and methods:
Patients who were admitted to IMCU between April 2019 and January 2021 were analyzed retrospectively. Sociodemographics, clinical characteristics, and blood parameters on admission were compared between the patients who died in IMCU and the others. Blood parameters at discharge were compared between survived and deceased individuals. Survival analysis was performed via Kaplan-Meier analysis. Blood parameters predicting mortality were determined by univariate and multivariate Cox regression analysis.
Results:
A total of 140 patients were included within the scope of this study. The median age was 72.5 years, and 77 (55%) of them were male and 63 (45%) of them were female. A total of 37 (26.4%) patients deceased in IMCU, and 40 patients (28.5%) were transferred to ICU. Higher platelet count (HR 3.454; 95% CI 1.383-8.625; p=0.008), procalcitonin levels (HR 3.083; 95% CI 1.158-8.206; p=0.024), and lower oxygen saturation (HR 4.121; 95% CI 2.018-8.414; p < 0.001) were associated with an increased risk of mortality in IMCU. At discharge from IMCU, higher procalcitonin levels (HR 2.809; 95% CI 1.216-6.487; p=0.016), lower platelet count (HR 2.269; 95% CI 1.012-5.085; p=0.047), and noninvasive mechanic ventilation requirement (HR 2.363; 95% CI 1.201-4.651; p=0.013) were associated with an increased risk of mortality. Median OS was found as 41 days. The overall survival rate was found 40% while the IMCU survival rate was 73.6%.
Conclusions:
IMCU seems to have a positive effect on survival in patients with severe COVID-19 infection. Close monitoring of these parameters and early intervention may improve survival rates and outcomes.
... According to the research, live but not inactivated SARS-CoV-2 virus-induced neutrophils produce NETs. It was found that virus penetration inside neutrophils and its replication occurred through the fusion of virus spike protein (S) and the angiotensin-converting enzyme (ACE2) and the cleavage of S protein by TMPRSS2 serine protease, the expression of which was also confirmed in neutrophils [96,97]. Furthermore, evidence suggests that NETs form the scaffolding for thrombus bound to von Willebrand factor (VWF), which is cleaved by the ADAMRS13 enzyme [98]. ...
Neutrophils—polymorphonuclear cells (PMNs) are the cells of the initial immune response and make up the majority of leukocytes in the peripheral blood. After activation, these cells modify their functional status to meet the needs at the site of action or according to the agent causing injury. They receive signals from their surroundings and “plan” the course of the response in both temporal and spatial contexts. PMNs dispose of intracellular signaling pathways that allow them to perform a wide range of functions associated with the development of inflammatory processes. In addition to these cells, some protein complexes, known as inflammasomes, also have a special role in the development and maintenance of inflammation. These complexes participate in the proteolytic activation of key pro-inflammatory cytokines, such as IL-1β and IL-18. In recent years, there has been significant progress in the understanding of the structure and molecular mechanisms behind the activation of inflammasomes and their participation in the pathogenesis of numerous diseases. The available reports focus primarily on macrophages and dendritic cells. According to the literature, the activation of inflammasomes in neutrophils and the associated death type—pyroptosis—is regulated in a different manner than in other cells. The present work is a review of the latest reports concerning the course of inflammasome activation and inflammatory cytokine secretion in response to pathogens in neutrophils, as well as the role of these mechanisms in the pathogenesis of selected diseases.
... За год, прошедший с момента начала пандемии, вызванной коронавирусом SARS-CoV-2, стало очевидным: орган зрения находится под ударом данной инфекции наряду с прочими органами и тканями. Это обусловлено тем, что белки, имеющие отношение к ренин-ангиотензин-альдостероновой системе (RAAS) и играющие ключевую роль при заражении SARS-CoV-2, широко распространены в тканях глаза: в пигментном эпителии [1], сетчатке [2][3][4][5][6] и водянистой влаге [7]. ...
Posterior eye segment involvement in COVID-19 has varied manifestations: vascular, inflammatory, and neuronal. All of them are triggered by SARS-CoV-2 virus but they cannot be viewed as exclusively specific to COVID-19. According to the literature, the mean age of the patients varies from 17 to 75 with the median of 50 years. The median duration between the appearance of ophthalmic symptoms and the detection of COVID-19 was 12 days. The disease affects both men and women equally. Direct exposure to the virus, immune-mediated tissue damage, activation of the coagulation system, the prothrombotic state caused by a viral infection, concomitant diseases and medications used in the treatment contribute to the development of eye pathologies. Ophthalmologists should be aware of the possible relations of posterior eye segment pathologies, orbit and neuro-ophthalmic disorders with SARS-CoV-2, as well as the possible exacerbation of chronic forms of inflammatory eye diseases and autoimmune disorders due to anti-COVID-19 vaccination.
... После заражения клеток SARSCoV-2 происходит уменьшение транскрипции мРНК АПФ2 и приводит к усилению выделения цитокинов, повреждению эндотелия и повышению проницаемости кровеносных сосудов [21,41]. ...
The coronavirus infection, COVID-19, caused by SARS-CoV-2 is associated not only with a wide range of respiratory syndromes, but also with a pronounced destructive effect on the blood vessels of the whole body. Age and concomitant pathology predispose to a more severe course of the disease. Endothelial damage, widespread vasculitis and thrombosis can be distinguished as general nonspecific pathomorphological changes developing in blood vessels under the influence of SARS-CoV-2. For the blood vessels of the lungs, in addition to alteration of the endothelium and thrombosis, angiogenesis of the cleaving (invagination) type was typical. The general mechanism of alteration of blood vessels and the development of vasculopathy is the direct cytopathic effect of the virus on endotheliocytes and immune-mediated damage to the endothelium, manifested by the development of endotheliitis, destruction of intercellular contacts of endothelial cells, their swelling and separation from the basement membrane, accompanied by endo- and perivascular inflammation. Molecular biological mechanisms of virus invasion involve various ways of its penetration into the cell and various forms of development of the inflammatory response with the participation of innate and acquired immunity reactions.
... Reactive Oxygen Species (ROS) produced as a result of membrane-bound NDPH oxidase stimulation by Ang II (Suhail et al., 2020). Consequently, Angiotensin 2 is degraded into Angiotensin (1-7) through ACE2, reduces OS via NDPH oxidase inhibition (Lovren et al., 2008). According to Sena et al., (2018) emphasized that, ACE2 bounding to COVID-19 down-regulates ACE2, resulting an elevated existence of superoxide species and consequent cellular damages, that could contain protein carbonylation, DNA oxidation, and lipid peroxidation. ...
Coronavirus disease 2019 (COVID-19) has rapidly spread across the globe since its outbreak in Wuhan, China, in 2019. Clinical evidence suggests higher oxidative stress in COVID-19 patients, and this worsening redox status which may contribute to disease progression. The present study aimed to investigate the oxidative Deoxyribonucleic acid damage in patients with mild and severe COVID-19 infection and to evaluate its relationship to the disease progression and severity. A case-control study was conducted from September 2021 to January 2022 in Duhok city, Kurdistan Region-Iraq. 180 individuals have participated. Among 88 COVID-19 cases, 92 healthy volunteers as the control group, with ages ranging (18-45) years. Patients were divided into two groups according to the severity of infection (mild cases, severe cases). Serum level of 8-OHdG and malondialdehyde (MDA) were assessed as oxidative stress biomarkers. Serum levels of 8-OHdG were considerably higher in patients with COVID-19 infection in comparison to the control group, (p<0.01). The further statistical analysis has revealed a significantly higher 8-OHdG in blood in female cases with severe COVID-19 infection compared cases with a mild infection, (p<0.01). Serum MDA levels in severe cases were higher, statistically significant when compared with the control group (p=0.007). Severe cases had higher level of MDA than in mild case, in male cases (p<0.05) in female cases (p<0.0001). The current data suggest that patients who were infected severely with COVID-19 are under huge oxidative stress attack. Analysis of data shows that severe cases of COVID-19 infection had significantly greater level of serum 8-OHdG than in healthy control subjects.
... Since ACE-2 has an important role in improving OS, the interaction of viral spike proteins and ACE-2 is critical for the viral replication cycle [7]. The reduction of angiotensin-II to angiotensin 1-7 by ACE-2 reduces the OS, as it inhibits NADPH oxidase [8]. When ACE-2 is bound to the spike protein, the cellular concentration of angiotensin-II increases; thereby, the risk for severe disease will also increase [9]. ...
Background/aim
Viral infections of the respiratory tract are generally related to many factors such as excessive production of cytokines, inflammation, cellular death, redox imbalance or oxidative stress. The aim of this study was to determine the serum levels of thiol and IMA in patients with severe COVID-19 pneumonia to evaluate oxidative stress.
Study design
This was a prospective, sectional cohort study conducted at a pandemics hospital between 01.01.2022 and 01.02.2022.
Methods
A total of 153 patients who had been confirmed with severe COVID-19 pneumonia in the emergency unit were prospectively analyzed. The control group was formed by 50 healthy volunteers with similar age and no chronic disease history. Thiol and IMA levels were statistically compared both in the patient and the control groups, and within the patient groups (survived and non-survival).
Results
While 96 out of 153 patients had survived, 57 patients had non-survival. There was a statistically significant distinction between the survived and non-survival patients with regard to Thiol and IMA levels (p < 0.001). The thiol levels in the patient group were significantly lower compared to the control group, and the IMA levels were significantly higher (p < 0.001). The sensitivity, specificity and NPV were 70.2%, 86.5% and 83% when thiol cut-off value was ≤345.2 μmol/L (AUC: 0.886, p < 0.001). The sensitivity, specificity and NPV were 70.2%, 85.4% and 82.8% when the IMA cut-off was >302.9 ABSU (AUC: 0.875, p < 0.001).
Conclusions
Our results demonstrate that thiol and IMA levels may be used as bioindicators for risk classification and mortality in patients with serious COVID-19 pneumonia.
... Polymorphism of the ACE-2 D-allele was associated with higher risk of essential hypertension and higher ACE-2 plasma levels were indicative of patients at higher cardiovascular risk [48,68,69]. The role of ACE-2 in the cardiovascular system is somewhat controversial as it is known to stabilize atherosclerotic plaques and lower blood pressure through the conversion of Ang II (vasoconstrictor) into Ang-(1-7) [70][71][72]. ...
Worldwide, up to 8.8 million excess deaths/year have been attributed to air pollution, mainly due to the exposure to fine particulate matter (PM). Traffic-related noise is an additional contributor to global mortality and morbidity. Both health risk factors substantially contribute to cardiovascular, metabolic and neuropsychiatric sequelae. Studies on the combined exposure are rare and urgently needed because of frequent co-occurrence of both risk factors in urban and industrial settings. To study the synergistic effects of PM and noise, we used an exposure system equipped with aerosol generator and loud-speakers, where C57BL/6 mice were acutely exposed for 3d to either ambient PM (NIST particles) and/or noise (aircraft landing and take-off events). The combination of both stressors caused endothelial dysfunction, increased blood pressure, oxidative stress and inflammation. An additive impairment of endothelial function was observed in isolated aortic rings and even more pronounced in cerebral and retinal arterioles. The increase in oxidative stress and inflammation markers together with RNA sequencing data indicate that noise particularly affects the brain and PM the lungs. The combination of both stressors has additive adverse effects on the cardiovascular system that are based on PM-induced systemic inflammation and noise-triggered stress hormone signaling. We demonstrate an additive upregulation of ACE-2 in the lung, suggesting that there may be an increased vulnerability to COVID-19 infection. The data warrant further mechanistic studies to characterize the propagation of primary target tissue damage (lung, brain) to remote organs such as aorta and heart by combined noise and PM exposure.
... Hal ini menunjukan adanya kerusakan endotel (Wang, 2018). Sebagai catatan, sel endotel juga memiliki ACE2 dan sel endotel merupakan sepertiga dari keseluruhan sel paru (Lovren, 2008;(Sluimer, 2008;Zeng, 2012). Permeabilitas mikrovaskular yang merupakan komplikasi dari rusaknya endotel dapat memfasilitasi invasi virus. ...
Novel coronavirus disease (COVID-19) merupakan penyakit saluran pernafasan akut baru yang disebabkan oleh virus SARSCoV-2, dengan manifestasi klinis berpa pneumonia akut pada paru dan dapat komplikasi berbagai macam organ seperti jantung, saluran nafas, darah, dan ginjal. Penyakit ini sangat menular dengan manifetasi dan komplikasi yang beraneka ragam dan menimbulkan ancaman bagi kesehatan masyarakat. Karena sering muncul bersama pneumonia akut, Gagal Ginjal Akut sangat berperan dalam prognosis pasien. Oleh karenanya, perhatian harus diberikan pada Gagal Ginjal Akut dalam COVID-19. Penelitian ini menggunakan metode review jurnal ilmiah mengenai COVID-19. Peneliti mencari jurnal menggunakan aplikasi Google scholar dan NCBI, dengan jurnal yang digunakan berkisar dari tahun 2000 sampai dengan tahun 2020. Artikel dalam literature review ini dianalisis, diekstraksi, dan disintesis serta kemudian dirangkum hasilnya. Dari hasil analisis ini diharapkan akan ditemukan kesimpulan yang dapat dijadikan dasar mengenai GGA sebagai komplikasi dari COVID-19. Gagal Ginjal Akut pada COVID-19 sangat sering terjadi terutama pada pasien berat atau yang mengalami kondisi kritis. Pemahaman kita mengenai pathogenesis Gagal Ginjal Akut pada COVID-19 masih sangat bersifat asumtif, berdasarkan penelitian sebelumnya dan 2 penyakit sebelumnya, yakni SARS dan MERS. Kerusakan ginjal dapat terjadi karena serangan langsung dari virus itu sendiri, atau dikarenakan badai sitokin yang disebabkan oleh abnormalitas system imun. Hipotensi atau dehidrasi, hipoksemia, sepsis, dan obat-obatan nefrotoksik juga dapat menyebabkan Gagal Ginjal Akut.
... The key receptor ACE2 is definitely expressed on numerous epithelial cells throughout the body, but with some of the pathology seen may also infect endothelial cells and perhaps some immune cells including neutrophils. 33,34 The incubation of neutrophils 34 or platelets 35 with SARS-CoV-2 leads to changes in effector function which could simply be the stimulation of membrane receptors for viral molecules. However, these same studies claimed that both neutrophils and platelets express ACE2, 34,35 making it plausible that these circulating cells could be infected by virus leading to some of the cardiovascular pathology described below. ...
Coronavirus disease 2019 (COVID‐19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and has resulted in more than 6 million deaths worldwide. COVID‐19 is a respiratory disease characterized by pulmonary dysfunction leading to acute respiratory distress syndrome (ARDs), as well as disseminated coagulation, and multi‐organ dysfunction. Neutrophils and neutrophil extracellular traps (NETs) have been implicated in the pathogenesis of COVID‐19. In this review, we highlight key gaps in knowledge, discuss the heterogeneity of neutrophils during the evolution of the disease, how they can contribute to COVID‐19 pathogenesis, and potential therapeutic strategies that target neutrophil‐mediated inflammatory responses.
... This hypercoagulable state most likely implies massive endothelial damage. Since endothelial cells comprise one-third of pulmonary cells [21] and they express ACE2 [22], the virus could penetrate them, causing their injury. Endothelial injury could cause increased vascular permeability, which can make viral penetration easier. ...
The massive expansion of the new coronavirus SARS-CoV-2 has urged countries to introduce lockdowns and set restrictive actions worldwide. The focus of the studies was to determine how COVID-19 induces damage to the lungs in order to find an alternative or adjuvant therapy that could lead to preventing COVID-19 or at least ameliorating it. This paper aims to survey the literature and provide new insights into behavioral and dietary habits that could influence the prevention of COVID-19. Maintaining an adequate mental health status, sleep, and taking moderate exercise are often disrupted in the conditions of lockdown and are followed by weakened immunity. Mediterranean and vegetarian diets are superior to other eating patterns in terms of immunity boosting and fighting COVID-19. Our study showed how adequate hydration, green tea intake, and supplementation with vitamins D, C, and E can increase our chances of avoiding the infection and even help us sleep better. Another focus of the research was on determining what level of hygiene really increases one’s chances of not contracting SARS-CoV-2, but this seems a little counter-intuitive at first. Since an immunocompromised state is a familiar predisposing factor for all contagious diseases, maintaining healthy behavioral and dietary habits could be a crucial step in boosting immunity and preventing COVID-19.
... 28 Therefore, endothelial ACE2 expression in the retina could be a possible target for viral antigens. 29,30 Hematogenous spread of the viral load may cause the destruction of ACE2 receptors. Diminished ACE2 expression in neurosensory retinal cells and the retinal vasculature may cause inflammation and oxidative stress, both of which could result in the impairment of neurovascular autoregulation, and may alter flow regulation in the retina, retinal pigment epithelium, choroid, and optic disc through the intraocular local RAS. ...
Objectives:
Retinal vascular complications have been described in patients with coronavirus disease 2019 (COVID-19). This study aimed to analyze retinal microvascular changes and their correlations with clinical findings.
Materials and methods:
This case-controlled study was conducted in a university hospital. The right eyes of 52 otherwise healthy patients recovered from COVID-19 and 42 healthy controls were examined with optical coherence tomography angiography. Mann-Whitney U test was used to compare vessel density (VD) and foveal avascular zone (FAZ) parameters. Associations with treatment choices, pneumonia, and laboratory findings were analyzed.
Results:
Twenty-nine patients (56%) and 18 healthy controls (43%) were men. Mean age of the COVID-19 group was 39.00±13.04 years. Twenty-two patients had pneumonia, 18 (35%) received hydroxychloroquine (HCQ), 17 (33%) received HCQ plus low-molecular-weight heparin (LMWH), and 10 (19%) received favipiravir. The patient group had lower parafoveal VD in the superficial capillary plexus (SCP) and lower parafoveal VD and perifoveal VD in the deep capillary plexus (DCP) than controls (p=0.003, p=0.004, p=0.001). FAZ area did not differ significantly (p=0.953). Perifoveal VD in the DCP was also significantly lower in the HCQ+LMWH group than the HCQ group (p=0.020) and in the presence of pneumonia (p=0.040). C-reactive protein (CRP) and ferritin levels were negatively correlated with perifoveal VD in the DCP (r=-0.445, p=0.023; r=-0.451, p=0.040). Ferritin was also negatively correlated with parafoveal VD in the SCP (r=-0.532, p=0.013).
Conclusion:
Parafoveal and perifoveal VD was found to be lower in the COVID-19 group. Presence of pneumonia, need for LMWH prophylaxis, and levels of CRP and ferritin were found to be negatively associated with retinal VD. Large-scale studies are needed to evaluate the clinical importance.
... Since ACE-2 has an important role in improving OS, the interaction of viral spike proteins and ACE-2 is critical for the viral replication cycle [7]. The reduction of angiotensin-II to angiotensin 1-7 by ACE-2 reduces the OS, as it inhibits NADPH oxidase [8]. When ACE-2 is bound to the spike protein, the cellular concentration of angiotensin-II increases; thereby, the risk for severe disease will also increase [9]. ...
... 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]. Pericytes-the 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. ...
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 influence COVID-19 by applying the Adverse Outcome Pathway (AOP) framework well-established in regulatory toxicology. This framework aims to model the sequence of events starting from an initial interaction of a stressor with the organism and the progress through key biological 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 patients 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 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.
While it is well-known that subjects with underlying cardiovascular disease as well as those with associated comorbidities have an increased susceptibility to worse outcomes during acute COVID-19 infection, the long-term cardiovascular impact of COVID-19 is still to be unravelled. A subset of patients continues to present with cardiopulmonary symptoms, mainly shortness of breath, chest pain and palpitations, months and even years after the acute infection. Furthermore, studies have revealed that a minority of patients have residual left and/or right ventricular dysfunction at follow-up, as well as deranged cardiac markers, mainly troponin and NT-proBNP levels. The chapter will explore the current evidence with regard to endothelial and myocardial dysfunction following COVID-19, discuss possible underlying pathophysiology, and suggest the management of patients with persistent cardiovascular symptomatology.
The renin-angiotensin system is involved in maintaining the body’s homeostasis across various functions. Its primary significance lies in blood pressure maintenance and cardiovascular functions, well-recognized for which many drug classes—such as angiotensin-converting enzyme inhibitors (ACE inhibitors), direct renin inhibitors, and angiotensin receptor blockers (AT blockers)—are widely used to manage diverse cardiovascular complications. The identification of ACE2 within the RAS led to the discovery of the non-classical RAS pathway. This pathway involves ACE2 activation, converting Angiotensin II to Angiotensin (1–7), which predominantly interacts with MAS receptors, countering the effects mediated by ACE. During the COVID-19 crisis, the role of ACE2 gained renewed attention among scientists, particularly in deciphering its downstream signaling effects. Research has extensively explored the role of ACE2 in several diseases such as hypertension, cardiac remodeling, stroke, diabetes, obesity, depression, Alzheimer’s, and Parkinson’s. Consequently, both ACE2 activators and inhibitors have been identified recently. However, as of now, no specific molecule has been approved to target ACE2 for treating diseases. The COVID-19 pandemic has reignited researchers’ interest in studying ACE2 signaling, shedding light on its diverse roles in different diseases. Consequently, ACE2 could emerge as an important therapeutic target for various medical conditions.
Diabetic vascular complications are prevalent and severe among diabetic patients, profoundly affecting both their quality of life and long-term prospects. These complications can be classified into macrovascular and microvascular complications. Under the impact of risk factors such as elevated blood glucose, blood pressure, and cholesterol lipids, the vascular endothelium undergoes endothelial dysfunction, characterized by increased inflammation and oxidative stress, decreased NO biosynthesis, endothelial-mesenchymal transition, senescence, and even cell death. These processes will ultimately lead to macrovascular and microvascular diseases, with macrovascular diseases mainly characterized by atherosclerosis (AS) and microvascular diseases mainly characterized by thickening of the basement membrane. It further indicates a primary contributor to the elevated morbidity and mortality observed in individuals with diabetes. In this review, we will delve into the intricate mechanisms that drive endothelial dysfunction during diabetes progression and its associated vascular complications. Furthermore, we will outline various pharmacotherapies targeting diabetic endothelial dysfunction in the hope of accelerating effective therapeutic drug discovery for early control of diabetes and its vascular complications.
Angiotensin-converting enzyme 2 (ACE2) is a counterregulator against ACE by converting angiotensin II (Ang II) to Ang-(1-7), and its down-regulation leads to endothelial dysfunction in the vascular system. In the present study, we investigated the effects of soybean protein isolate hydrolysate (SPIH) on Ang II-induced endothelial dysfunction with its underlying mechanisms via ACE2 activation in human umbilical vein endothelial cells (HUVECs). We further screened potential ACE2 activating peptides by peptidomics analysis combined with bioinformatics tools. Results showed that SPIH remarkably attenuated Ang II-induced cell migration from 129 to 92%, decreased the ROS level from 2.22-fold to 1.45-fold, and increased NO concentration from 31.4 ± 0.7 to 43.7 ± 0.1 μM in HUVECs. However, these beneficial effects were reversed by ACE2 inhibitor MLN-4760 to a certain extent, indicating the modulation of ACE2. Further results revealed that SPIH (1 mg/mL) significantly increased the expression and activity of ACE2 and two novel ACE2 activating peptides with different mechanisms were explored from SPIH. IVPQ and IAVPT (50 μM) enhanced ACE2 activity, and only IVPQ (50 μM) increased ACE2 protein expression in HUVECs. These findings furthered our understanding of the antihypertensive mechanism of SPIH mediating the ACE2 activation on vascular endothelium.
Angiotensin converting enzyme 2 (ACE2) played a critical role in regulating renin‐angiotensin‐aldosterone system (RAAS). In this research, ⁶⁸ Ga‐cyc‐DX600 was synthesized as PET tracer of ACE2 imaging. ACE2 positron emission tomography/magnetic resonance (PET/MR) was preliminary administered on twelve healthy volunteers, and the images were normalized and registered to establish the standard model of ACE2 PET. In diseased conditions, ⁶⁸ Ga‐cyc‐DX600 PET and ¹⁸ F‐FDG PET were compared for COVID‐19 (one in acute phase and three in post‐COVID), anemia ( n = 1) and malignancies ( n = 2) to evaluate the diagnostic efficiency. ⁶⁸ Ga‐cyc‐DX600 PET was of a definite ACE2 dependence. For the tracer uptake of ACE2 PET/MR of female and male, differences existed in salivary glands, upper respiratory tract and kidneys, meanwhile, age, and body mass index (BMI) were also the confounding factors. RAAS‐related tissue and organs were of the relatively higher tracer uptake, such as SUV mean of cardiac chamber (3.786 ± 1.495), liver (5.342 ± 2.267), spleen (4.465 ± 2.508), and kidney (4.906 ± 1.619 for female and 8.431 ± 5.179 for male). For COVID‐19, ACE2 PET revealed ACE2 fluctuations, particularly in the susceptible organs, including liver, spleen and testis. In the case of anemia, the activated local RAS in the bone marrow was of diffuse high tracer uptake. ACE2 PET of malignancies added supplementary information to FDG PET. ⁶⁸ Ga‐cyc‐DX600‐based ACE2 PET models were established for visually monitoring of whole‐body ACE2 expression. The feasibility of ACE2 PET in supervising disease was primarily proved in COVID‐19, anemia and malignancies as providing a comprehensive view on the disease process and functional recovery.
Introduction:
We assess the correlation between COVID-19 infection and erection and evaluate the effect of aging and comorbidities on the male sexuality of patients with COVID-19 infection.
Methods:
100 patients were enrolled and diagnosed with COVID-19 based on reverse transcription-polymerase chain reaction tests of oropharyngeal and nasopharyngeal swabs according to the WHO guidelines. The International Index of Erectile Function (IIEF-5) questionnaire was used to evaluate sexual function.
Results:
Patients were divided into two groups: the first group of 42 patients <50 years of age with a mean age (±SD) of 35.83 ± 7.8 and the second group of 58 patients ≥50 years of age with a mean age of 58.64 ± 7.7. The mean (±SD) IIEF in the first group pre-COVID-19 infection was 14.2 ± 2.37 while post-COVID-19 was 8.7 ± 2.77, 11.3 ± 2.9, 12.1 ± 3.02 at 1, 3, 6 months, respectively (p < 0.001), while in the second group, the mean (±SD) IIEF pre-COVID-19 infection was 10.04 ± 4.62 while post-COVID was 5.0 ± 2.1, 6.56 ± 2.6, 8.18 ± 2.04 at 1, 3, 6 months, respectively (p < 0.001). On multivariate analysis, old patients infected with COVID-19 and associated with comorbidities such as diabetes mellitus (OR = 8.53, CI = 0.00-2.01), hypertension (OR = 3.908, CI = 0.000-3.07), ischemic heart disease (OR = 2.863, CI = 0.000-2.68), and liver disease (OR = 0.670, CI = 0.000-1.670) were significantly correlated to erectile dysfunction (p < 0.001).
Conclusion:
COVID-19 significantly affects erection mostly in older patients with comorbidities, leading to subsequent use of oral and intracavernosal injection therapy for erectile dysfunction.
Data shows that HIV/AIDS infection among adolescents in countries such as Africa is still high, especially in populations aged 15–19 years. Women and girls are more vulnerable to HIV infection than men. No single way can effectively prevent or manage HIV/AIDS in adolescents. It takes various biomedical, behavioral, and structural aspects into a comprehensive intervention package. We review a strategy to decrease transmission of HIV among adolescents, the so-called SICEP, including screening, integrated health care, conducting and monitoring, eliminating, and providing quality health care.
This chapter explores the implications for the health of humans, animals, and the environment derived from the provision and utilization of conventional public services (e.g., healthcare and water and sanitation supply) and non-conventional services (e.g., provision of green spaces). Public services are services like education, health, and sanitation, entitled to a population, and so are important for achieving development goals. Here, the integration of public services under the One Health (OH) perspective, which is key for promoting health and early detection of risks of future epidemics, is exemplified by the cases of food systems, land use, and land cover change. The discussion section of this chapter addresses how to reduce the risks of future epidemics by making public services enablers of health. Finally, we call for more integrative research and action under the OH approach.
Panik bozukluğu (PB), DSM-IV-TR (Diagnostic and Stastistical
Manual of Mental Disorders) ’de anksiyete bozuklukları başlığının altında
sınıflandırılmaktadır. Panik bozukluk hastalığının genel bir özelliği yenileyici
nitelikte, hiç beklenmeyen bir şekilde meydana gelen panik ataklardır. Söz
konusu ataklar uzun sürmeyen, çok bunaltıcı ya da korku süreçleridir. Panik
atağı esnasında bireyler, başlarına bir felaket gelebileceği hissine kapılırlar.
Çarpıntı, göğüs ağrısı, nefes darlığı benzeri şikayetleri sebebiyle yaygın bir
şekilde kalp krizi geçirip, ölebilecekleri düşüncesine kapılırlar. Birey taze bir
nöbet geçirebilme korkusu ile (bekleme anksiyetesi), kalabalık bir ortamdan,
evin dışında yalnız kalmaktan ya da yolculuk yapmaktan sakınır ki bu durum
“agorafobi’’ diye adlandırılmaktadır. Panik Bozukluk 20‟li yaşlarda başlasa
bile genel olarak yaşamın belirsiz bir sürecinde başlayabilmektedir. Sosyal
ve mesleki fonksiyonlarda mühim problemlere sebep olabilmektedir (Kaplan
ve ark., 1994; Kaplan, 2007; Köroğlu, 2007). Son yıllarda serbest oksijen
radikallerinin nöropsikiyatrik olan rahatsızlıkların patofizyolojisinde mühim
etkisi olduğuna yönelik bilgiler zamanla artış göstermiştir.
Bipolar bozukluk (BB), tekrarlayan gerek mani, gerek hipomani ve
gerekse de depresif epizodlarla karakterize edilmiş olan kronik biçimli
duygudurum bozukluğudur. Bipolar Bozukluk teşhisi alan hastaların yaklaşık
olarak %80'i ilk duygudurum epizodundan sonraki 2 sene içerisinde yeni bir
hastalık dönemi daha yaşadıkları açıklanmıştır (Nıce, 2014). Bipolar
Bozukluk, büyük ölçüde yeti yitimine sebep olan ve de bozucu seyri esnasında
büyük ölçüde mortalite tehlikesi taşıyan kronik ve nöropsikiyatrik
hastalıklardan biridir. Dünya Sağlık Örgütü’nce (WHO) iş gücü kaybına en
fazla neden olan hastalıklar içinde kabul görmüştür (Mathers ve ark., 2004;
Weissman ve ark., 1996). Hastalıkların yüksek olan morbidite ve de
mortaliteleri, doğruya doğru veya dolaylı olarak maliyetleri yüksek olan
mühim ölçüde ekonomik yönünden ve sosyal yönünden yük meydana
getirmektedir (Saha ve ark., 2005, Barbato, 1998). Bilhassa çinko (Zn) ve
bakır (Cu) gibi eser elementler; canlı olan organizmalarda pek çok enzim
yönünden vazgeçilmez olan kofaktörlerdir. Fakat nöropsikiyatrik olan
hastalıkların farklı türlerde seviyeleri yorumlanmış ve seviyelerinin olması
gereken seviyenin aşağısına düşmesi veya yukarısına çıkması halinde bipolar
bozukluk ve de şizofreninin de içinde olmak üzere çeşitli nörolojik ve
psikiyatrik bozuklukların etiyoloji ve patofizyolojisinde etkili olabileceği
gösterilmiştir.
Familial Mediterranean fever (FMF) is the most familiar and
widespread inheritable auto-inflammatory disease. This inherited disease is
indicated by recurrent self-limiting attacks of serosal surfaces and result in
inflammation. Inflammation is the physiological resistance that the organism
responds to every kind of deleterious stimulus. Vitamin D deficiency or insufficiency have vital role in the
initiation and enduring of certain autoimmune diseases. According to prior
pertinent studies, vitamin D levels in adult FMF patients as well as children
with FMF manifest hypovitaminosis D as compared with healthy peers. The frequency of vitamin D deficiency in children and adults with
familial Mediterranean fever (FMF) is demonstrated and found that the serum
25-hydroxyvitamin D levels were significantly lower in FMF patients than the
healthy controls and incremental colchicine dose appears to negatively affect
vitamin D levels.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.