Saccular intracranial aneurysm (sIA) rupture leads to subarachnoid haemorrhage and is preceded by chronic inflammation and atherosclerotic changes of the sIA wall. Increased lymphangiogenesis has been detected in atherosclerotic extracranial arteries and in abdominal aortic aneurysms, but the presence of lymphatic vessels in sIAs has remained unexplored. Here we studied the presence of lymphatic vessels in 36 intraoperatively resected sIAs (16 unruptured and 20 ruptured), using immunohistochemical and immunofluorescence stainings for lymphatic endothelial cell (LEC) markers. Of these LEC-markers, both extracellular and intracellular LYVE-1-, podoplanin-, VEGFR-3-, and Prox1-positive stainings were detected in 83%, 94%, 100%, and 72% of the 36 sIA walls, respectively. Lymphatic vessels were identified as ring-shaped structures positive for one or more of the LEC markers. Of the sIAs, 78% contained lymphatic vessels positive for at least one LEC marker. The presence of LECs and lymphatic vessels were associated with the number of CD68+ and CD163+ cells in the sIA walls, and with the expression of inflammation indicators such as serum amyloid A, myeloperoxidase, and cyclo-oxygenase 2, with the presence of a thrombus, and with the sIA wall rupture. Large areas of VEGFR-3 and α-smooth muscle actin (αSMA) double-positive cells were detected in medial parts of the sIA walls. Also, a few podoplanin and αSMA double-positive cells were discovered. In addition, LYVE-1 and CD68 double-positive cells were detected in the sIA walls and in the thrombus revealing that certain CD68+ macrophages are capable of expressing LEC markers. This study demonstrates for the first time the presence of lymphatic vessels in human sIA walls. Further studies are needed to understand the role of lymphatic vessels in the pathogenesis of sIA.
Hyperactive poly(ADP-ribose) polymerases (PARP) promote ischemic heart failure (IHF) after myocardial infarction (MI). However, the role of tankyrases (TNKSs), members of the PARP family, in pathogenesis of IHF remains unknown. We investigated the expression and activation of TNKSs in myocardium of IHF patients and MI rats. We explored the cardioprotective effect of TNKS inhibition in an isoproterenol-induced zebrafish HF model. In IHF patients, we observed elevated TNKS2 and DICER and concomitant upregulation of miR-34a-5p and miR-21-5p in non-infarcted myocardium. In a rat MI model, we found augmented TNKS2 and DICER in the border and infarct areas at the early stage of post-MI. We also observed consistently increased TNKS1 in the border and infarct areas and destabilized AXIN in the infarct area from 4 weeks onward, which in turn triggered Wnt/β-catenin signaling. In an isoproterenol-induced HF zebrafish model, inhibition of TNKS activity with XAV939, a TNKSs-specific inhibitor, protected against ventricular dilatation and cardiac dysfunction and abrogated overactivation of Wnt/β-catenin signaling and dysregulation of miR-34a-5p induced by isoproterenol. Our study unravels a potential role of TNKSs in the pathogenesis of IHF by regulating Wnt/β-catenin signaling and possibly modulating miRNAs and highlights the pharmacotherapeutic potential of TNKS inhibition for prevention of IHF.
Neutrophil proteinase 3 (PR3) is a multifunctional neutral serine protease involved in the regulation of pro-inflammatory processes, but its potential causal roles in the lipid-driven responses in atherosclerosis have remained unexplored. This study aimed to investigate the presence of PR3 in human atherosclerotic lesions and the ability of this protease to modify the structure and functions of LDL and HDL particles in vitro. Coronary artery segments were collected from autopsied subjects and immunostained for PR3. Atherosclerotic lesions but not normal intima contained PR3. Incubation of LDL particles with the PR3 led to extensive degradation of their apoB-100 component and strongly increased their binding strength to isolated human aortic proteoglycans in vitro. Moreover, cultured human monocyte-derived macrophages avidly ingested the PR3-modified LDL particles and were converted into foam cells. Incubation of HDL particles with PR3 led to proteolysis of their major apolipoproteins (apoA-I, apoA-II, and apoE) and impaired their ability to promote cholesterol efflux from the macrophage foam cells. We conclude that PR3 is present in human atherosclerotic lesions and that this neutral serine protease has proatherogenic properties. Thus, by proteolytically modifying LDL and HDL particles, PR3 may promote cholesterol accumulation both extra- and intracellularly in atherosclerotic lesions, and so contribute to the lipid-driven component of atherogenesis.
Cells are continuously exposed to tissue-specific extrinsic forces that are counteracted by cell-intrinsic force generation through the actomyosin cytoskeleton and alterations in the material properties of various cellular components, including the nucleus. Forces impact nuclei both directly through inducing deformation, which is sensed by various mechanosensitive components of the nucleus, as well as indirectly through the actomyosin cytoskeleton and mechanosensitive pathways activated in the cytoplasm. To view this SnapShot, open or download the PDF.
On July 23, 2022, World Health Organization (WHO) declared the current monkeypox outbreak a Public Health Emergency of International Concern (PHEIC). Less than a week later New York and San Francisco declared a state of emergency due to an alarming rise in the number of monkeypox cases. By July 29, 2022; 22, 141 cases of monkeypox had been reported globally in the countries that have not been reported this disease historically. Of these cases 4,906 were reported from the USA. We discuss in this letter about repurposing role of cholesterol lowering drugs.
PaxlovidTM is a promising antiviral oral medication for patients at a high risk of a severe form of COVID-19. Regarding COVID-19 patients who have hypercholesterolemia and are at high or very high risk for an acute atherothrombotic cardiovascular event, we are highlighting patients with heterozygous familial hypercholesterolemia as an example of severe hypercholesterolemia. Unfortunately, the concomitant use of Paxlovid and a statin, which is highly dependent on cytochrome P4507A (CYP3A) for clearance, may result in significant drug interactions. Since an abrupt withdrawal of statin use may cause serious negative rebound effects on the cardiovascular system, it is essential to continue statin treatment also during the 5-day Paxlovid treatment period. During Paxlovid treatment, simvastatin and lovastatin need to be substituted with another statin, such as pravastatin or fluvastatin, while a reduction of the dose of atorvastatin and rosuvastatin is recommended.
ABSTRACT Based on separate protective mechanisms related to lipid metabolism, viral cell entry and inflammation, fibrate treatment might be advantageous among patients who have been taking fibrates before SARS-CoV-2 infection and continue taking them during the infection. Based on published data on hospitalized COVID-19 patients, we recommend that the clinicians should ask their patients with metabolic syndrome who are already taking fibrates to continue fibrate treat- ment during the COVID-19 illness. This recommendation applies to both outpatients and hospi- talized patients. However, results from the ongoing randomized controlled trials (RCTs) using fenofibrate treatment for the prevention or treatment of COVID-19 have yet to prove that fenofi- brate is clinically significant for this indication. KEY MESSAGES � The role of fibrates as a repurpose to treat SARS-CoV-2 is under investigation in at least three ongoing RCTs. � Obesity, diabetes, hypertension and dyslipidaemia, individually or clustered as a discrete phenotype, the metabolic syndrome, typically associate with a more severe course of COVID-19. � Fibrate treatment seems to be most advantageous among patients who have been taken fibrates before SARS-CoV-2 infection and are continuing to take them during the infection. � We recommend that the clinicians encourage their patients who are already taking fibrate to continue using the drug throughout the COVID-19 illness.
Vascular endothelial growth factor C (VEGF-C) induces lymphangiogenesis via VEGF receptor-3 (VEGFR3), encoded by the most frequently mutated gene in human primary lymphedema. Angiopoietins (Angs) and their Tie receptors regulate lymphatic vessel development and mutations of the ANGPT2 gene were recently found in human primary lymphedema. However, the mechanistic basis of Ang2 activity in lymphangiogenesis is not fully understood. Here we used gene deletion, blocking antibodies, transgene induction and gene transfer to study how Ang2, its Tie2 receptor and Tie1 regulate lymphatic vessels. We discovered that VEGF-C-induced Ang2 secretion from lymphatic endothelial cells (LECs) is involved in full Akt activation downstream of phosphoinositide-3 kinase (PI3K). Neonatal deletion of genes encoding the Tie receptors or Ang2 in LECs, or administration of Ang2 blocking antibody decreased VEGFR3 presentation on LECs and inhibited lymphangiogenesis. A similar effect was observed in LECs upon deletion of PI3K catalytic p110α subunit or with small molecule inhibition of a constitutively active PI3K located downstream of Ang2. Deletion of Tie receptors or blockade of Ang2 decreased VEGF-C-induced lymphangiogenesis also in adult mice. Our results reveal important crosstalk between the VEGF-C and Ang signaling pathways and suggest new avenues for therapeutic manipulation of lymphangiogenesis by targeting Ang2-Tie-PI3K signaling.
Objectives: Impaired protein kinase signaling is a hallmark of ischemic heart disease (IHD). Inadequate understanding of the pathological mechanisms limits the development of therapeutic approaches. We aimed to identify the key cardiac kinases and signaling pathways in patients with IHD with an effort to discover potential therapeutic strategies. Methods: Cardiac kinase activity in IHD left ventricle (LV) and the related signaling pathways were investigated by kinomics, transcriptomics, proteomics, and integrated multi-omics approach. Results: Protein kinase A (PKA) and protein kinase G (PKG) ranked on top in the activity shift among the cardiac kinases. In the IHD LVs, PKA activity decreased markedly compared with that of controls (62% reduction, p = 0.0034), whereas PKG activity remained stable, although the amount of PKG protein increased remarkably (65%, p = 0.003). mRNA levels of adenylate cyclases (ADCY 1, 3, 5, 9) and cAMP-hydrolysing phosphodiesterases (PDE4A, PDE4D) decreased significantly, although no statistically significant alterations were observed in that of PKGs (PRKG1 and PRKG2) and guanylate cyclases (GUCYs). The gene expression of natriuretic peptide CNP decreased remarkably, whereas those of BNP, ANP, and neprilysin increased significantly in the IHD LVs. Proteomics analysis revealed a significant reduction in protein levels of “Energy metabolism” and “Muscle contraction” in the patients. Multi-omics integration highlighted intracellular signaling by second messengers as the top enriched Reactome pathway. Conclusion: The deficiency in cAMP/PKA signaling pathway is strongly implicated in the pathogenesis of IHD. Natriuretic peptide CNP could be a potential therapeutic target for the modulation of cGMP/PKG signaling.
In mice, embryonic dermal lymphatic development is well understood and used to study gene functions in lymphangiogenesis. Notch signaling is an evolutionarily conserved pathway that modulates cell fate decisions, which has been shown to both inhibit and promote dermal lymphangiogenesis. Here, we demonstrate distinct roles for Notch4 signaling versus canonical Notch signaling in embryonic dermal lymphangiogenesis. Actively growing embryonic dermal lymphatics expressed NOTCH1, NOTCH4, and DLL4 which correlated with Notch activity. In lymphatic endothelial cells (LECs), DLL4 activation of Notch induced a subset of Notch effectors and lymphatic genes, which were distinctly regulated by Notch1 and Notch4 activation. Treatment of LECs with VEGF-A or VEGF-C upregulated Dll4 transcripts and differentially and temporally regulated the expression of Notch1 and Hes / Hey genes. Mice nullizygous for Notch4 had an increase in the closure of the lymphangiogenic fronts which correlated with reduced vessel caliber in the maturing lymphatic plexus at E14.5 and reduced branching at E16.5. Activation of Notch4 suppressed LEC migration in a wounding assay significantly more than Notch1, suggesting a dominant role for Notch4 in regulating LEC migration. Unlike Notch4 nulls, inhibition of canonical Notch signaling by expressing a dominant negative form of MAML1 (DNMAML) in Prox1+ LECs led to increased lymphatic density consistent with an increase in LEC proliferation, described for the loss of LEC Notch1 . Moreover, loss of Notch4 did not affect LEC canonical Notch signaling. Thus, we propose that Notch4 signaling and canonical Notch signaling have distinct functions in the coordination of embryonic dermal lymphangiogenesis.
Background and aims; Glutamine synthetase (GLUL), the sole generator of glutamine, is a metabolic nexus molecule also involved in atherosclerosis. We recently demonstrated a 2.2-fold upregulation of GLUL mRNA in stroke-causing carotid plaques when compared with plaques from asymptomatic patients. Here we compared in the same cohort GLUL mRNA expression with plaque gross morphology, and the colocalization of immunodetectable GLUL protein with histopathological changes and molecular and mechanical mediators linked to plaque development. Methods; Endarterectomy specimens from 19 asymptomatic and 24 stroke patients were sectioned longitudinally and immunostained for GLUL, CD68, α-smooth muscle actin, iron, heme oxygenase-1 and CD163, and graded semiquantitatively in every 1 mm². The amounts of cholesterol clefts and erythrocytes were graded. The fibrous cap thickness within each 1 mm² area was measured. The association between the local pathological findings was analyzed by a hierarchical mixed modelling approach. Results; The previously found correlation between GLUL mRNA and clinical symptomatology was supported by the increased GLUL mRNA in diseased tissue and increased local GLUL immunoreactivity in areas with multiple different atherosclerotic changes. A longer symptom-to-operation time correlated with lower GLUL mRNA (Rs = −0.423, p=0.050) but few outliers had a significantly higher GLUL mRNA levels, which persisted throughout the post-symptomatic period. Plaque ulceration associated with 1.8-fold higher GLUL mRNA (p=0.006). Macrophages were the main GLUL immunoreactive cells. GLUL immunostaining colocalized with erythrocytes, iron, CD163, and heme oxygenase-1. The correlations between local variables were consistent in both asymptomatic and stroke-causing plaques. An inverse correlation was found between the fibrous cap thickness and local GLUL immunoreactivity (p=0.012). Considerable variability in interplaque expression pattern of GLUL was present. Conclusions; Our results link connect macrophage GLUL expression with carotid plaque features characterizing plaque vulnerability.
The healthcare system of Ukraine was already suffering from several shortfalls before February 2022, but the war of aggression started by the Russian leadership is poised to inflict a further severe blow that will have long-lasting consequences for the health of all Ukrainians. In pre-war Ukraine, noncommunicable diseases (NCDs) contributed to 91% of deaths, especially cardiovascular diseases (67%). Ukrainians have a high prevalence of risk factors for NCDs ranking among the highest levels reported by the World Health Organization (WHO) in the European (EU) Region. Cardiovascular disease is one of the key health risks for the conflict-affected Ukrainian population due to significant limitations in access to health care and interruptions in the supply of medicines and resources. The excess mortality observed during the COVID-19 pandemic, due to a combination of viral illness and chronic disease states, is bound to increase exponentially from poorly treated NCDs. In this report, we discuss the impact of the war on the public health of Ukraine and potential interventions to provide remote health assistance to the Ukrainian population.
Cells and tissues generate and are exposed to various mechanical forces that act across a range of scales, from tissues to cells to organelles. Forces provide crucial signals to inform cell behaviour during development and adult tissue homeostasis, and alterations in forces and in their downstream mechanotransduction pathways can influence disease progression. Recent advances have been made in our understanding of the mechanisms by which forces regulate chromatin organization and state, and of the mechanosensitive transcription factors that respond to the physical properties of the cell microenvironment to coordinate gene expression, cell states and behaviours. These insights highlight the relevance of mechanosensitive transcriptional regulation to physiology, disease and emerging therapies. Dupont and Wickström review the current understanding of how mechanical forces regulate chromatin state and gene expression and discuss the importance of this mechanosensitive gene regulation to physiology and disease.
Blood vessels are thought to form either by de novo vasculogenesis or by angiogenesis from pre-existing blood vessels. Research now finds that anal fin blood vessels form by endothelial transdifferentiation from lymphatic vessels.
When compared with non-FH patients who have suffered an acute SARS-CoV-2 infection, in FH patients a hypercoagulable state may persist for even longer periods after the infection. This assumption is relevant because the endothelial cells have been exposed to a lifelong high LDL-C concentration, and often also to an elevated Lp(a) level, which jointly cause endothelial dysfunction even in childhood. This can be particularly harmful in the FH patients whose LDL-C-lowering therapy is lacking or sub-optimal, and among those FH patients who also have a highly elevated serum Lp(a) level. Thrombus formationin an arterial, venous, or microvascular vascular segment, is likely to occur with greater frequency among FH patients not only because of a pre-existing endothelial dysfunction but also as a result of the acute direct viral endothelial damage and the hypercoagulability state during the post-COVID period.Although reliable epidemiological data are not yet available, it is obvious that the entire FH population, i.e., about 30 million FH patients worldwide, are at an increased risk of serious vascular complications which can occur after COVID-19. Consequently, when a clinician encounters an FH patient with symptoms that match with those typical of the post-COVID syndrome, it is of importance that the clinician ascertains that lipid-lowering pharmacotherapy is being taken regulary, is adequate, and follows the current guidelines. In this context, it is relevant to remember that statins also act as mild antithrombotic medications. When appropriate, PCSK9 inhibition may be included in the lipid-lowering therapy even among younger FH patients with COVID-19 and thereafter, as, unlike statins, the PCSK9 inhibitors can also reduce the level of serum Lp(a).
Significance The pseudokinase integrin-linked kinase (ILK) is a central component of focal adhesions, cytoplasmic multiprotein complexes that integrate and transduce biochemical and mechanical signals from the extracellular environment into the cell and vice versa. However, the precise molecular functions, particularly the mechanosensory properties of ILK and the significance of retained adenosine triphosphate (ATP) binding, are still unclear. Combining molecular-dynamics simulations with cell biology, we establish a role for ATP binding to pseudokinases. We find that ATP promotes the structural stability of ILK, allosterically influences the interaction between ILK and its binding partner parvin at adhesions, and enhances the mechanoresistance of this complex. On the cellular level, ATP binding facilitates efficient traction force buildup, focal adhesion stabilization, and efficient cell migration.
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