Melatonin, cardiovascular disease and COVID-19: A potential therapeutic strategy?

2020 ◽  
Vol 3 (3) ◽  
pp. 318-321 ◽  
Author(s):  
Alberto Dominguez-Rodriguez ◽  
Pedro Abreu-Gonzalez ◽  
Paul E Marik ◽  
Russel J Reiter
Keyword(s):  
Reactive Oxygen Species ◽  
Cardiovascular Disease ◽  
Endothelial Dysfunction ◽  
Angiotensin Converting Enzyme ◽  
Therapeutic Strategy ◽  
Oxygen Species ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Ros Formation ◽  
Membrane Bound

The mechanism for SARS-CoV-2 infection is the requisite binding of the virus to the membrane-bound form of angiotensin-converting enzyme 2 (ACE2) and internalization of the complex by the host cell. SARS-CoV-2 induced endothelial dysfunction and cardiovascular injury are probably initiated by increases in the phosphorylation levels of JAK2 and STAT3 and resultant reactive oxygen species (ROS) formation. These pathological alterations are speculated to be strikingly reversed by melatonin

scholarly journals Angiotensin-converting enzyme 2 (ACE2) levels in relation to risk factors for COVID-19 in two large cohorts of patients with atrial fibrillation

2020 ◽  
Vol 41 (41) ◽  
pp. 4037-4046 ◽  
Author(s):  
Lars Wallentin ◽  
Johan Lindbäck ◽  
Niclas Eriksson ◽  
Ziad Hijazi ◽  
John W Eikelboom ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Cardiovascular Disease ◽  
Angiotensin Converting Enzyme ◽  
Association Studies ◽  
Cell Surface Receptor ◽  
Genome Wide Association Studies ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Cellular Expression ◽  
Male Sex

Abstract Aims The global COVID-19 pandemic is caused by the SARS-CoV-2 virus entering human cells using angiotensin-converting enzyme 2 (ACE2) as a cell surface receptor. ACE2 is shed to the circulation, and a higher plasma level of soluble ACE2 (sACE2) might reflect a higher cellular expression of ACE2. The present study explored the associations between sACE2 and clinical factors, cardiovascular biomarkers, and genetic variability. Methods and results Plasma and DNA samples were obtained from two international cohorts of elderly patients with atrial fibrillation (n = 3999 and n = 1088). The sACE2 protein level was measured by the Olink Proteomics® Multiplex CVD II96 × 96 panel. Levels of the biomarkers high-sensitive cardiac troponin T (hs-cTnT), N-terminal probrain natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), C-reactive protein, interleukin-6, D-dimer, and cystatin-C were determined by immunoassays. Genome-wide association studies were performed by Illumina chips. Higher levels of sACE2 were statistically significantly associated with male sex, cardiovascular disease, diabetes, and older age. The sACE2 level was most strongly associated with the levels of GDF-15, NT-proBNP, and hs-cTnT. When adjusting for these biomarkers, only male sex remained associated with sACE2. We found no statistically significant genetic regulation of the sACE2 level. Conclusions Male sex and clinical or biomarker indicators of biological ageing, cardiovascular disease, and diabetes are associated with higher sACE2 levels. The levels of GDF-15 and NT-proBNP, which are associated both with the sACE2 level and a higher risk for mortality and cardiovascular disease, might contribute to better identification of risk for severe COVID-19 infection.

Angiotensin-converting enzyme 2 is subject to post-transcriptional regulation by miR-421

2014 ◽  
Vol 127 (4) ◽  
pp. 243-249 ◽  
Author(s):  
Daniel W. Lambert ◽  
Louise A. Lambert ◽  
Nicola E. Clarke ◽  
Nigel M. Hooper ◽  
Karen E. Porter ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Transcriptional Regulation ◽  
Angiotensin Converting Enzyme ◽  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Post Transcriptional Regulation ◽  
Cardiac Myofibroblasts

The molecular mechanisms controlling the expression of ACE2, a critical regulator of cardiovascular homoeostasis, remain poorly defined. In the present study, we show that miR-421 regulates expression of ACE2 in cardiac myofibroblasts, identifying a possible new therapeutic target in cardiovascular disease.

scholarly journals Most exposed: the endothelium in chronic kidney disease

2019 ◽  
Vol 35 (9) ◽  
pp. 1478-1487 ◽  
Author(s):  
Marc Vila Cuenca ◽  
Peter L Hordijk ◽  
Marc G Vervloet
Keyword(s):  
Risk Factors ◽  
Reactive Oxygen Species ◽  
Cardiovascular Disease ◽  
Chronic Kidney Disease ◽  
Endothelial Dysfunction ◽  
Kidney Disease ◽  
Oxygen Species ◽  
Pathological Changes ◽  
Endothelial Lining ◽  
Traditional Risk Factors

Abstract Accumulating evidence indicates that the pathological changes of the endothelium may contribute to the development of cardiovascular complications in chronic kidney disease (CKD). Non-traditional risk factors related to CKD are associated with the incidence of cardiovascular disease, but their role in uraemic endothelial dysfunction has often been disregarded. In this context, soluble α-Klotho and vitamin D are of importance to maintain endothelial integrity, but their concentrations decline in CKD, thereby contributing to the dysfunction of the endothelial lining. These hormonal disturbances are accompanied by an increment of circulating fibroblast growth factor-23 and phosphate, both exacerbating endothelial toxicities. Furthermore, impaired renal function leads to an increment of inflammatory mediators, reactive oxygen species and uraemic toxins that further aggravate the endothelial abnormalities and in turn also inhibit the regeneration of disrupted endothelial lining. Here, we highlight the distinct endothelial alterations mediated by the abovementioned non-traditional risk factors as demonstrated in experimental studies and connect these to pathological changes in CKD patients, which are driven by endothelial disturbances, other than atherosclerosis. In addition, we describe therapeutic strategies that may promote restoration of endothelial abnormalities by modulating imbalanced mineral homoeostasis and attenuate the impact of uraemic retention molecules, inflammatory mediators and reactive oxygen species. A clinical perspective on endothelial dysfunction in CKD may translate into reduced structural and functional abnormalities of the vessel wall in CKD, and ultimately improved cardiovascular disease.

Angiotensin converting enzyme-2 confers endothelial protection and attenuates atherosclerosis

2008 ◽  
Vol 295 (4) ◽  
pp. H1377-H1384 ◽  
Author(s):  
Fina Lovren ◽  
Yi Pan ◽  
Adrian Quan ◽  
Hwee Teoh ◽  
Guilin Wang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Endothelial Cells ◽  
Reactive Oxygen Species Production ◽  
Oxygen Species ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Apolipoprotein E Knockout Mice ◽  
Species Production

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.

scholarly journals Why Is COVID-19 More Severe in Patients With Diabetes? The Role of Angiotensin-Converting Enzyme 2, Endothelial Dysfunction and the Immunoinflammatory System

2021 ◽  
Vol 7 ◽  
Author(s):  
Jacob Roberts ◽  
Antonia L. Pritchard ◽  
Andrew T. Treweeke ◽  
Adriano G. Rossi ◽  
Nicole Brace ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Angiotensin Converting Enzyme ◽  
Inflammatory Responses ◽  
Severe Form ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Increased Risk ◽  
Patients With Diabetes ◽  
Inflammatory Processes ◽  
Meta Analyses

Meta-analyses have indicated that individuals with type 1 or type 2 diabetes are at increased risk of suffering a severe form of COVID-19 and have a higher mortality rate than the non-diabetic population. Patients with diabetes have chronic, low-level systemic inflammation, which results in global cellular dysfunction underlying the wide variety of symptoms associated with the disease, including an increased risk of respiratory infection. While the increased severity of COVID-19 amongst patients with diabetes is not yet fully understood, the common features associated with both diseases are dysregulated immune and inflammatory responses. An additional key player in COVID-19 is the enzyme, angiotensin-converting enzyme 2 (ACE2), which is essential for adhesion and uptake of virus into cells prior to replication. Changes to the expression of ACE2 in diabetes have been documented, but they vary across different organs and the importance of such changes on COVID-19 severity are still under investigation. This review will examine and summarise existing data on how immune and inflammatory processes interplay with the pathogenesis of COVID-19, with a particular focus on the impacts that diabetes, endothelial dysfunction and the expression dynamics of ACE2 have on the disease severity.

scholarly journals Angiotensin converting enzyme 2 is a novel target of the γ-secretase complex

2020 ◽  
Author(s):  
Alberto Bartolomé ◽  
Jiani Liang ◽  
Pengfei Wang ◽  
David D. Ho ◽  
Utpal B. Pajvani
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Renin Angiotensin System ◽  
Structural Similarity ◽  
Ectodomain Shedding ◽  
Converting Enzyme ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Membrane Bound ◽  
Novel Target ◽  
Functional Receptor

AbstractAngiotensin converting enzyme 2 (ACE2) is a key regulator of the renin-angiotensin system, but also the functional receptor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on structural similarity with other γ-secretase (γS) targets, we hypothesized that ACE2 may be affected by γS proteolytic activity. We found that after ectodomain shedding, ACE2 is targeted for intramembrane proteolysis by γS, releasing a soluble ACE2 C-terminal fragment. Consistently, chemical or genetic inhibition of γS results in the accumulation of a membrane-bound fragment of ectodomain-deficient ACE2. Although chemical inhibition of γS does not alter SARS-CoV-2 cell entry, these data point to a novel pathway for cellular ACE2 trafficking.

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