COVID-19, ACE2, and the cardiovascular consequences.
ABSTRACT: The novel SARS coronavirus SARS-CoV-2 pandemic may be particularly deleterious to patients with underlying cardiovascular disease (CVD). 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. Recognition that ACE2 is the coreceptor for the coronavirus has prompted new therapeutic approaches to block the enzyme or reduce its expression to prevent the cellular entry and SARS-CoV-2 infection in tissues that express ACE2 including lung, heart, kidney, brain, and gut. ACE2, however, is a key enzymatic component of the renin-angiotensin-aldosterone system (RAAS); ACE2 degrades ANG II, a peptide with multiple actions that promote CVD, and generates Ang-(1-7), which antagonizes the effects of ANG II. Moreover, experimental evidence suggests that RAAS blockade by ACE inhibitors, ANG II type 1 receptor antagonists, and mineralocorticoid antagonists, as well as statins, enhance ACE2 which, in part, contributes to the benefit of these regimens. In lieu of the fact that many older patients with hypertension or other CVDs are routinely treated with RAAS blockers and statins, new clinical concerns have developed regarding whether these patients are at greater risk for SARS-CoV-2 infection, whether RAAS and statin therapy should be discontinued, and the potential consequences of RAAS blockade to COVID-19-related pathologies such as acute and chronic respiratory disease. The current perspective critically examines the evidence for ACE2 regulation by RAAS blockade and statins, the cardiovascular benefits of ACE2, and whether ACE2 blockade is a viable approach to attenuate COVID-19.
Project description:It has been established that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses angiotensin-converting enzyme 2 (ACE2), a membrane-bound regulatory peptide, for host cell entry. Renin-angiotensin-aldosterone system (RAAS) inhibitors have been reported to increase ACE2 in type 2 pneumocyte pulmonary tissue. Controversy exists for the continuation of ACE inhibitors, angiotensin II receptor blockers, and mineralocorticoid receptor antagonists in the current pandemic. ACE2 serves as a regulatory enzyme in maintaining homeostasis between proinflammatory angiotensin II and anti-inflammatory angiotensin 1,7 peptides. Derangements in these peptides are associated with cardiovascular disease and are implicated in the progression of acute respiratory distress syndrome. Augmentation of the ACE2/Ang 1,7 axis represents a critical target in the supportive management of coronavirus disease 2019-associated lung disease. Observational data describing the use of RAAS inhibitors in the setting of SARS-CoV-2 have not borne signals of harm to date. However, equipoise persists, requiring an analysis of novel agents including recombinant human-ACE2 and existing RAAS inhibitors while balancing ongoing controversies associated with increased coronavirus infectivity and virulence.
Project description:ACE inhibitors (ACEis) and angiotensin receptor blockers (ARBs) are standard-of-care treatments for hypertension and diabetes, common comorbidities among hospitalized patients with coronavirus disease 2019 (COVID-19). Their use in the setting of COVID-19 has been heavily debated due to potential interactions with ACE2, an enzyme that links the pro-inflammatory and anti-inflammatory arms of the renin angiotensin system, but also the entryway by which severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) invades cells. ACE2 expression is altered by age, hypertension, diabetes, and the virus itself. This study integrated available information about the renin angiotensin aldosterone system (RAAS) and effects of SARS-CoV-2 and its comorbidities on ACE2 into a mechanistic mathematical model and aimed to quantitatively predict effects of ACEi/ARBs on the RAAS pro-inflammatory/anti-inflammatory balance. RAAS blockade prior to SARS-CoV-2 infection is predicted to increase the mas-AT1 receptor occupancy ratio up to 20-fold, indicating that in patients already taking an ACEi/ARB before infection, the anti-inflammatory arm is already elevated while the pro-inflammatory arm is suppressed. Predicted pro-inflammatory shifts in the mas-AT1 ratio due to ACE2 downregulation by SARS-CoV-2 were small relative to anti-inflammatory shifts induced by ACEi/ARB. Predicted effects of changes in ACE2 expression with comorbidities of diabetes, hypertension, or aging on mas-AT1 occupancy ratio were also relatively small. Last, predicted changes in the angiotensin (Ang(1-7)) production rate with ACEi/ARB therapy, comorbidities, or infection were all small relative to exogenous Ang(1-7) infusion rates shown experimentally to protect against acute lung injury, suggesting that any changes in the ACE2-Ang(1-7)-mas arm may not be large enough to play a major role in COVID-19 pathophysiology.
Project description:Angiotensin converting enzyme 2 (ACE2) is the recognized host cell receptor responsiblefor mediating infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ACE2bound to tissue facilitates infectivity of SARS-CoV-2; thus, one could argue that decreasing ACE2tissue expression would be beneficial. However, ACE2 catalytic activity towards angiotensin I (AngI) and II (Ang II) mitigates deleterious effects associated with activation of the renin-angiotensinaldosteronesystem (RAAS) on several organs, including a pro-inflammatory status. At the tissuelevel, SARS-CoV-2 (a) binds to ACE2, leading to its internalization, and (b) favors ACE2 cleavage toform soluble ACE2: these actions result in decreased ACE2 tissue levels. Preserving tissue ACE2activity while preventing ACE2 shredding is expected to circumvent unrestrained inflammatoryresponse. Concerns have been raised around RAAS modulators and their effects on ACE2expression or catalytic activity. Various cellular and animal models report conflicting results invarious tissues. However, recent data from observational and meta-analysis studies in SARS-CoV-2-infected patients have concluded that RAAS modulators do not increase plasma ACE2 levels orsusceptibility to infection and are not associated with more severe diseases. This review presentsour current but evolving knowledge of the complex interplay between SARS-CoV-2 infection, ACE2levels, modulators of RAAS activity and the effects of RAAS modulators on ACE2 expression.
Project description:People with underlying conditions, including hypertension, obesity, and diabetes, are especially susceptible to negative outcomes after infection with coronavirus SARS-CoV-2, which causes COVID-19. Hypertension and respiratory inflammation are exacerbated by the Renin-Angiotensin-Aldosterone System (RAAS), which normally protects from rapidly dropping blood pressure via Angiotensin II (Ang II) produced by the enzyme Ace. The Ace paralog Ace2 degrades Ang II, counteracting its chronic effects, and serves as the SARS-CoV-2 receptor. <i>Ace</i>, the coronavirus, and COVID-19 comorbidities all regulate <i>Ace2</i>, but we do not yet understand how. To exploit zebrafish (<i>Danio rerio</i>) to help understand the relationship of the RAAS to COVID-19, we must identify zebrafish orthologs and co-orthologs of human RAAS genes and understand their expression patterns. To achieve these goals, we conducted genomic and phylogenetic analyses and investigated single cell transcriptomes. Results showed that most human RAAS genes have one or more zebrafish orthologs or co-orthologs. Results identified a specific type of enterocyte as the specific site of expression of zebrafish orthologs of key RAAS components, including Ace, Ace2, Slc6a19 (SARS-CoV-2 co-receptor), and the Angiotensin-related peptide cleaving enzymes Anpep (receptor for the common cold coronavirus HCoV-229E), and Dpp4 (receptor for the Middle East Respiratory Syndrome virus, MERS-CoV). Results identified specific vascular cell subtypes expressing Ang II receptors, <i>apelin</i>, and <i>apelin receptor</i> genes. These results identify genes and cell types to exploit zebrafish as a disease model for understanding mechanisms of COVID-19.
Project description:The objective of this review is to give an overview of the pathophysiological effects of the Coronavirus Disease 2019 (COVID-19) in relation to hypertension (HT), with a focus on the Renin-Angiotensin-Aldosterone System (RAAS) and the MAS receptor. HT is a multifactorial disease and a public health burden, as it is a risk factor for diseases like stroke, coronary artery disease, and heart failure, leading to 10.4 million deaths yearly. Blood pressure is regulated by the RAAS. The system consists of two counter-regulatory axes: ACE/ANG-II/AT<sub>1</sub> R and ACE2/ANG-(1-7)/MAS. The main regulatory protein in balancing the RAAS is angiotensin-converting enzyme 2 (ACE2). The protein also functions as the main mediator of endocytosis of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the host cell. SARS-CoV-2 is the cause of COVID-19 and has caused a worldwide pandemic; however, the treatment and prophylaxis of COVID-19 are limited. Several drugs and vaccines are currently being tested in clinical trials with a few already approved by EMA and FDA. HT is a major risk factor regarding the severity and fatality of COVID-19, and the RAAS plays an important role in COVID-19 infection since SARS-CoV-2 can lead to a dysregulation of the system by reducing the ACE2 expression. The exact mechanisms of HT in relation to COVID-19 remain uncertain, and more research is needed for further elucidation.
Project description:The last decade was crucial for our understanding of the renin–angiotensin–aldosterone system (RAAS) as a two-axis, counter-regulatory system, divided into the classical axis, formed by angiotensin-converting enzyme (ACE), angiotensin II (Ang II), and the angiotensin type 1 receptor (AT1R), and the alternative axis comprising angiotensin-converting enzyme 2 (ACE2), angiotensin-(1-7) (Ang-(1-7)), and the Mas receptor. Breakthrough discoveries also took place, with other RAAS endopeptides being described, including alamandine and angiotensin A. In this review, we characterize the two RAAS axes and the role of their components in pediatric kidney diseases, including childhood hypertension (HTN), pediatric glomerular diseases, congenital abnormalities of the kidney and urinary tract (CAKUT), and chronic kidney disease (CKD). We also present recent findings on potential interactions between the novel coronavirus, SARS-CoV-2, and components of the RAAS, as well as potential implications of coronavirus disease 2019 (COVID-19) for pediatric kidney diseases.
Project description:The novel severe acute respiratory syndrome (SARS) coronavirus SARS-CoV-2 walks the planet causing the rapid spread of the CoV disease 2019 (COVID-19) that has especially deleterious consequences for the patients with underlying cardiovascular diseases (CVDs). Entry of the SARS-CoV-2 into the host cell involves interaction of the virus (via the receptor-binding domain (RBD) of its spike glycoprotein) with the membrane-bound form of angiotensin-converting enzyme 2 (ACE2) followed by the virus-ACE2 complex internalization by the cell. Since ACE2 is expressed in various tissues, such as brain, gut, heart, kidney, and lung, and since these organs represent obvious targets for the SARS-CoV-2 infection, therapeutic approaches were developed to either inhibit ACE2 or reduce its expression as a means of prevention of the virus entry into the corresponding host cells. The problem here is that in addition to be a receptor for the SARS-CoV-2 entry into the host cells, ACE2 acts as a key component of the renin-angiotensin-aldosterone system (RAAS) aimed at the generation of a cascade of vasoactive peptides coordinating several physiological processes. In RAAS, ACE2 degrades angiotensin II, which is a multifunctional CVD-promoting peptide hormone and converts it to a heptapeptide angiotensin-(1-7) acting as the angiotensin II antagonist. As protein multifunctionality is commonly associated with the presence of flexible or disordered regions, we analyze here the intrinsic disorder predisposition of major players related to the SARS-CoV-2 - RAAS axis. We show that all considered proteins contain intrinsically disordered regions that might have specific functions. Since intrinsic disorder might play a role in the functionality of query proteins and be related to the COVID-19 pathogenesis, this work represents an important disorder-based outlook of an interplay between the renin-angiotensin-aldosterone system and SARS-CoV-2. It also suggests that consideration of the intrinsic disorder phenomenon should be added to the modern arsenal of means for drug development.
Project description:Angiotensin Converting Enzyme2 is the cell surface binding site for the coronavirus SARS-CoV-2, which causes COVID-19. We propose that an imbalance in the action of ACE1- and ACE2-derived peptides, thereby enhancing angiotensin II (Ang II) signalling is primary driver of COVID-19 pathobiology. ACE1/ACE2 imbalance occurs due to the binding of SARS-CoV-2 to ACE2, reducing ACE2-mediated conversion of Ang II to Ang peptides that counteract pathophysiological effects of ACE1-generated ANG II. This hypothesis suggests several approaches to treat COVID-19 by restoring ACE1/ACE2 balance: (a) AT receptor antagonists; (b) ACE1 inhibitors (ACEIs); (iii) agonists of receptors activated by ACE2-derived peptides (e.g. Ang (1-7), which activates MAS1); (d) recombinant human ACE2 or ACE2 peptides as decoys for the virus. Reducing ACE1/ACE2 imbalance is predicted to blunt COVID-19-associated morbidity and mortality, especially in vulnerable patients. Importantly, approved AT antagonists and ACEIs can be rapidly repurposed to test their efficacy in treating COVID-19. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.
Project description:The coronavirus disease 2019 (COVID-19) pandemic is caused by a newly emerged coronavirus (CoV) called Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). COVID-19 patients with cardiovascular disease (CVD) comorbidities have significantly increased morbidity and mortality. The use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor type 1 blockers (ARBs) improve CVD outcomes; however, there is concern that they may worsen the prognosis of CVD patients that become infected with SARS-CoV-2 because the virus uses the ACE2 receptor to bind to and subsequently infect host cells. Thus, some health care providers and media sources have questioned the continued use of ACE inhibitors and ARBs. In this brief review, we discuss the effect of ACE inhibitor-induced bradykinin on the cardiovascular system, on the renin-angiotensin-aldosterone system (RAAS) regulation in COVID-19 patients, and analyze recent clinical studies regarding patients treated with RAAS inhibitors. We propose that the application of RAAS inhibitors for COVID-19 patients with CVDs may be beneficial rather than harmful.
Project description:Pharmacological blockade of the renin–angiotensin–aldosterone system (RAAS) with angiotensin-converting enzyme (ACE)-inhibitors and angiotensin receptor blockers (ARBs) are cornerstone treatments in several cardiovascular disease entities . The RAAS is a central regulator of blood pressure, consisting of two counterregulatory pathways, commonly described as classical and nonclassical, respectively . The main effect of classical RAAS activation is the generation of angiotensin (Ang)-II by ACE . In contrast, non-classical RAAS activation results in cleavage of Ang-II by angiotensin converting enzyme-2 (ACE2) to form angiotensin 1–7, which directly counteracts the effects of classical RAAS activation . Critically ill #COVID19 patients display markedly increased alternative angiotensin pathway activity compared to healthy controls, reflected by increased blood ACE2 levels as well as decreased angiotensin-II and enhanced angiotensin-1–7 formationhttps://bit.ly/2MU1z4z