Interaction between the apelinergic system and ACE2 in the cardiovascular system: therapeutic implications

2020 ◽  
Vol 134 (17) ◽  
pp. 2319-2336 ◽  
Author(s):  
Paulami Chatterjee ◽  
Mahmoud Gheblawi ◽  
Kaiming Wang ◽  
Jeannie Vu ◽  
Palsa Kondaiah ◽  
...  
Keyword(s):  
Physiological Role ◽  
Renin Angiotensin System ◽  
Protective Effects ◽  
Inotropic Effects ◽  
Angiotensin Converting Enzyme 2 ◽  
Therapeutic Implications ◽  
Transplant Vasculopathy ◽  
Prognostic Utility ◽  
Artery Disease ◽  
Plasma Apelin

Abstract The apelinergic system is widely expressed and acts through autocrine and paracrine signaling to exert protective effects, including vasodilatory, metabolic, and inotropic effects on the cardiovascular (CV) system. The apelin pathway’s dominant physiological role has delineated therapeutic implications for coronary artery disease, heart failure (HF), aortic aneurysm, pulmonary arterial hypertension (PAH), and transplant vasculopathy. Apelin peptides interact with the renin–angiotensin system (RAS) by promoting angiotensin converting enzyme 2 (ACE2) transcription leading to increased ACE2 protein and activity while also antagonizing the effects of angiotensin II (Ang II). Apelin modulation of the RAS by increasing ACE2 action is limited due to its rapid degradation by proteases, including ACE2, neprilysin (NEP), and kallikrein. Apelin peptides are hence tightly regulated in a negative feedback manner by ACE2. Plasma apelin levels are suppressed in pathological conditions, but its diagnostic and prognostic utility requires further clinical exploration. Enhancing the beneficial actions of apelin peptides and ACE2 axes while complementing existing pharmacological blockade of detrimental pathways is an exciting pathway for developing new therapies. In this review, we highlight the interaction between the apelin and ACE2 systems, discuss their pathophysiological roles and potential for treating a wide array of CV diseases (CVDs).

scholarly journals Alamandine: Potential Protective Effects in SARS-CoV-2 Patients

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Ava Soltani Hekmat ◽  
Kazem Javanmardi
Keyword(s):  
Pulmonary Fibrosis ◽  
Renin Angiotensin System ◽  
The Body ◽  
Host Cells ◽  
Protective Effects ◽  
Ang Ii ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Anti Inflammatory ◽  
G Protein Coupled

Coronavirus disease 2019 (COVID-19) can occur due to contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 has no confined treatment and, consequently, has high hospitalization and mortality rates. Moreover, people who contract COVID-19 present systemic inflammatory spillover. It is now known that COVID-19 pathogenesis is linked to the renin-angiotensin system (RAS). COVID-19 invades host cells via the angiotensin-converting enzyme 2 (ACE2) receptor—as such, an individual’s susceptibility to COVID-19 increases alongside the upregulation of this receptor. COVID-19 has also been associated with interstitial pulmonary fibrosis, which leads to acute respiratory distress, cardiomyopathy, and shock. These outcomes are thought to result from imbalances in angiotensin (Ang) II and Ang-(1-7)/alamandine activity. ACE2, Ang-(1-7), and alamandine have potent anti-inflammatory properties, and some SARS-CoV-2 patients exhibit high levels of ACE2 and Ang-(1-7). This phenomenon could indicate a failing physiological response to prevent or reduce the severity of inflammation-mediated pulmonary injuries. Alamandine, which is another protective component of the RAS, has several health benefits owing to its antithrombogenic, anti-inflammatory, and antifibrotic characteristics. Alamandine alleviates pulmonary fibrosis via the Mas-related G protein-coupled receptor D (MrgD). Thus, a better understanding of this pathway could uncover novel pharmacological strategies for altering proinflammatory environments within the body. Following such strategies could inhibit fibrosis after SARS-CoV-2 infection and, consequently, prevent COVID-19.

scholarly journals The renin-angiotensin system: going beyond the classical paradigms

2019 ◽  
Vol 316 (5) ◽  
pp. H958-H970 ◽  
Author(s):  
Robson Augusto Souza Santos ◽  
Gavin Y. Oudit ◽  
Thiago Verano-Braga ◽  
Giovanni Canta ◽  
Ulrike Muscha Steckelings ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
Protective Effects ◽  
Ang Ii ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Renin Angiotensin ◽  
Amino Terminal ◽  
Angiotensin Peptides ◽  
Protective Actions

Thirty years ago, a novel axis of the renin-angiotensin system (RAS) was unveiled by the discovery of angiotensin-(1−7) [ANG-(1−7)] generation in vivo. Later, angiotensin-converting enzyme 2 (ACE2) was shown to be the main mediator of this reaction, and Mas was found to be the receptor for the heptapeptide. The functional analysis of this novel axis of the RAS that followed its discovery revealed numerous protective actions in particular for cardiovascular diseases. In parallel, similar protective actions were also described for one of the two receptors of ANG II, the ANG II type 2 receptor (AT2R), in contrast to the other, the ANG II type 1 receptor (AT1R), which mediates deleterious actions of this peptide, e.g., in the setting of cardiovascular disease. Very recently, another branch of the RAS was discovered, based on angiotensin peptides in which the amino-terminal aspartate was replaced by alanine, the alatensins. Ala-ANG-(1−7) or alamandine was shown to interact with Mas-related G protein-coupled receptor D, and the first functional data indicated that this peptide also exerts protective effects in the cardiovascular system. This review summarizes the presentations given at the International Union of Physiological Sciences Congress in Rio de Janeiro, Brazil, in 2017, during the symposium entitled “The Renin-Angiotensin System: Going Beyond the Classical Paradigms,” in which the signaling and physiological actions of ANG-(1−7), ACE2, AT2R, and alatensins were reported (with a focus on noncentral nervous system-related tissues) and the therapeutic opportunities based on these findings were discussed.

scholarly journals Decreased Plasma Levels of Angiotensin-Converting Enzyme Among Patients With Bipolar Disorder

2021 ◽  
Vol 15 ◽  
Author(s):  
Marsal Sanches ◽  
Gabriela D. Colpo ◽  
Valeria A. Cuellar ◽  
Taya Bockmann ◽  
Deevakar Rogith ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Angiotensin Converting Enzyme ◽  
Plasma Levels ◽  
Renin Angiotensin System ◽  
Cross Sectional Study ◽  
Healthy Controls ◽  
Converting Enzyme ◽  
Cross Sectional ◽  
Angiotensin Converting Enzyme 2 ◽  
Therapeutic Implications

BackgroundDysfunctions in the renin-angiotensin system (RAS) seem to be involved in the pathophysiology of several mental illness, including schizophrenia and mood disorders. We carried out a cross-sectional study assessing the levels of RAS-related molecules among bipolar disorder (BD) patients compared to healthy controls.Methodsour sample consisted of 30 outpatients with BD type 1 (10 males, 20 females, age = 35.53 ± 10.59 years, 14 euthymic, 16 experiencing mood episodes) and 30 healthy controls (10 males, 20 females, age = 34.83 ± 11.49 years). Plasma levels of angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2), angiotensin-II (Ang II), and angiotensin (1–7) [Ang-(1–7)] were determined by ELISA.ResultsBD patients experiencing ongoing mood episodes had significantly lower ACE levels compared to controls (median: 459.00 vs. 514.10, p < 0.05). There was no association between the levels of these biomarkers and clinical parameters.ConclusionOur findings support the involvement of RAS dysfunction in the pathophysiology of BD. Considering the potential therapeutic implications linked to a better understanding of the role of RAS dysfunction in BD, studies allowing a better characterization of RAS-related molecules level and activity across different mood states are of high interest.

scholarly journals Renin-Angiotensin System Blockade In The Coronavirus Disease 2019 Pandemic

2021 ◽  
Author(s):  
Jordana B Cohen ◽  
Andrew M South ◽  
Hossam A Shaltout ◽  
Matthew R Sinclair ◽  
Matthew A Sparks
Keyword(s):  
Viral Entry ◽  
Renin Angiotensin System ◽  
Adverse Outcomes ◽  
Host Cells ◽  
Protective Effects ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Renin Angiotensin ◽  
Epidemiologic Evidence

ABSTRACT In the early months of the coronavirus disease 2019 (COVID-19) pandemic, a hypothesis emerged suggesting that pharmacologic inhibitors of the renin-angiotensin system (RAS) may increase COVID-19 severity. This hypothesis was based on the role of angiotensin-converting enzyme 2 (ACE2), a counter-regulatory component of the RAS, as the binding site for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), allowing viral entry into host cells. Extrapolations from prior evidence led to speculation that upregulation of ACE2 by RAS blockade may increase the risk of adverse outcomes from COVID-19. However, counterarguments pointed to evidence of potential protective effects of ACE2 and RAS blockade with regard to acute lung injury, as well as substantial risks from discontinuing these commonly used and important medications. Here we provide an overview of classic RAS physiology and the crucial role of ACE2 in systemic pathways affected by COVID-19. Additionally, we critically review the physiologic and epidemiologic evidence surrounding the interactions between RAS blockade and COVID-19. We review recently published trial evidence and propose important future directions to improve upon our understanding of these relationships.

scholarly journals The Significance of Angiotensin-Converting Enzyme-2 (ACE2) in SARSCov-2 Infection and COVID-19

Coronaviruses ◽  
2020 ◽  
Vol 01 ◽  
Author(s):  
Carolina Restini ◽  
Trevor Belavek ◽  
Rafael Bernal ◽  
Vanessa Ibrahim ◽  
Kelly Irwin ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Renin Angiotensin System ◽  
Cell Receptor ◽  
Host Cells ◽  
World Health ◽  
Protective Effects ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Health Organization

: The new coronavirus was first reported in 2019 (China) and officially announced by the World Health Organization as a pandemic in March 2020. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the pneumonia-associated illnesses and shares structural homology with the related Severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1). One of the mechanisms for SARS-Cov-1 and -2 infection is mediated by the angiotensin-converting enzyme-2 (ACE2) cell receptor, enabling the virus to enter the host cells. ACE2 is an isoform of the angiotensin-converting enzyme 1 (ACE). The actions of ACE2 counterbalance the classic renin-angiotensin system (RAS) axis through the production of Ang 1-7, which promotes cardiovascular, renal, and lung-protective effects. The ACE2 is not the only route for SARS-CoV-2 to enter the host cells. However, due to its roles in the RAS and its participation in the SARS-CoV-2 virulence, ACE2 has gained attention regarding viral mechanisms of pathogenesis, effects of drugs that interfere with the RAS, and as a potential target for therapeutic strategies for the damages caused by SARSCoV-2 infection. Among other tissues, ACE2 gene expression seems to be increased in the lungs upon SARS-CoV-2 infection; however, amid other variables, expression and/or activity of ACE2 is shown as a disease, sex, and age-dependent. The present review covers critical aspects for a comprehensive understanding of ACE2 and its current involvement in SARS-CoV-2 infection and the development of COVID-19.

The Angiotensin-Converting Enzyme 2/Angiotensin-(1–7)/Mas receptor axis: A potential target for treating thrombotic diseases

2012 ◽  
Vol 108 (12) ◽  
pp. 1089-1096 ◽  
Author(s):  
Rodrigo Fraga-Silva ◽  
Danielle Da Silva ◽  
Fabrizio Montecucco ◽  
François Mach ◽  
Nikolaos Stergiopulos ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Drug Targets ◽  
Therapeutic Potential ◽  
Renin Angiotensin System ◽  
Protective Effects ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Mas Receptor ◽  
Promising Target ◽  
Drug Treatments

SummaryDespite many therapeutic advances leading to increasingly effective drug treatments, thrombotic events (such as ischaemic stroke, pulmonary embolism, deep venous thrombosis and acute myocardial infarction) still represent a major worldwide cause of morbidity and mortality. Remarkable effort has been made to identify new drug targets. There is growing evidence indicating that the recently described counter-regulator axis of the renin-angiotensin system (RAS), composed of Angiotensin-Converting Enzyme 2 (ACE2), Angiotensin-(1–7) and the Mas receptor, has protective effects against thrombosis. In addition, it could be considered as a promising target for treating or preventing this disease. In this narrative review, we focused on the recent findings of the role of the ACE2/Angiotensin-(1–7)/Mas axis on the haemostatic process and its therapeutic potential.

ACE2 as therapeutic agent

2020 ◽  
Vol 134 (19) ◽  
pp. 2581-2595
Author(s):  
Qiuhong Li ◽  
Maria B. Grant ◽  
Elaine M. Richards ◽  
Mohan K. Raizada
Keyword(s):  
Therapeutic Agent ◽  
Renin Angiotensin System ◽  
Peptide Hormone ◽  
Experimental Models ◽  
Electrolyte Balance ◽  
Ang Ii ◽  
Angiotensin Converting Enzyme 2 ◽  
Beneficial Effects ◽  
Overwhelming Evidence ◽  
Future Challenges

Abstract The angiotensin-converting enzyme 2 (ACE2) has emerged as a critical regulator of the renin–angiotensin system (RAS), which plays important roles in cardiovascular homeostasis by regulating vascular tone, fluid and electrolyte balance. ACE2 functions as a carboxymonopeptidase hydrolyzing the cleavage of a single C-terminal residue from Angiotensin-II (Ang-II), the key peptide hormone of RAS, to form Angiotensin-(1-7) (Ang-(1-7)), which binds to the G-protein–coupled Mas receptor and activates signaling pathways that counteract the pathways activated by Ang-II. ACE2 is expressed in a variety of tissues and overwhelming evidence substantiates the beneficial effects of enhancing ACE2/Ang-(1-7)/Mas axis under many pathological conditions in these tissues in experimental models. This review will provide a succinct overview on current strategies to enhance ACE2 as therapeutic agent, and discuss limitations and future challenges. ACE2 also has other functions, such as acting as a co-factor for amino acid transport and being exploited by the severe acute respiratory syndrome coronaviruses (SARS-CoVs) as cellular entry receptor, the implications of these functions in development of ACE2-based therapeutics will also be discussed.

A Review of Angiotensin Receptor Blocker-based Therapies at all Levels of Cardiovascular Risk

2011 ◽  
Vol 7 (4) ◽  
pp. 254 ◽  
Author(s):  
Giuliano Tocci ◽  
Lorenzo Castello ◽  
Massimo Volpe ◽  
◽  
◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Ventricular Hypertrophy ◽  
Renin Angiotensin System ◽  
Left Ventricular ◽  
Clinical Settings ◽  
Angiotensin Ii Receptor ◽  
Angiotensin System ◽  
Receptor Blockers ◽  
Artery Disease

The renin–angiotensin system (RAS) has a key role in the maintenance of cardiovascular homeostasis, and water and electrolyte metabolism in healthy subjects, as well as in several diseases including hypertension, left ventricular hypertrophy and dysfunction, coronary artery disease, renal disease and congestive heart failure. These conditions are all characterised by abnormal production and activity of angiotensin II, which represents the final effector of the RAS. Over the last few decades, accumulating evidence has demonstrated that antihypertensive therapy based on angiotensin II receptor blockers (ARBs) has a major role in the selective antagonism of the main pathological activities of angiotensin II. Significant efforts have been made to demonstrate that blocking the angiotensin II receptor type 1 (AT1) subtype receptors through ARB-based therapy results in proven benefits in different clinical settings. In this review, we discuss the main benefits of antihypertensive strategies based on ARBs in terms of their efficacy, safety and tolerability.

scholarly journals Outcomes of COVID-19 Hospitalized Patients Previously Treated with Renin-Angiotensin System Inhibitors

2020 ◽  
Vol 9 (11) ◽  
pp. 3472 ◽  
Author(s):  
Elena-Mihaela Cordeanu ◽  
Lucas Jambert ◽  
Francois Severac ◽  
Hélène Lambach ◽  
Jonathan Tousch ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
Severe Pneumonia ◽  
University Hospital ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Renin Angiotensin ◽  
Previously Treated ◽  
The Impact ◽  
Harmful Effects ◽  
Observation Period

(1) Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) penetrates respiratory epithelium through angiotensin-converting enzyme-2 binding, raising concerns about the potentially harmful effects of renin–angiotensin system inhibitors (RASi) on Human Coronavirus Disease 2019 (COVID-19) evolution. This study aimed to provide insight into the impact of RASi on SARS-CoV-2 outcomes in patients hospitalized for COVID-19. (2) Methods: This was a retrospective analysis of hospitalized adult patients with SARS-CoV-2 infection admitted to a university hospital in France. The observation period ended at hospital discharge. (3) Results: During the study period, 943 COVID-19 patients were admitted to our institution, of whom 772 were included in this analysis. Among them, 431 (55.8%) had previously known hypertension. The median age was 68 (56–79) years. Overall, 220 (28.5%) patients were placed under mechanical ventilation and 173 (22.4%) died. According to previous exposure to RASi, we defined two groups, namely, “RASi” (n = 282) and “RASi-free” (n = 490). Severe pneumonia (defined as leading to death and/or requiring intubation, high-flow nasal oxygen, noninvasive ventilation, and/or oxygen flow at a rate of ≥5 L/min) and death occurred more frequently in RASi-treated patients (64% versus 53% and 29% versus 19%, respectively). However, in a propensity score-matched cohort derived from the overall population, neither death (hazard ratio (HR) 0.93 (95% confidence interval (CI) 0.57–1.50), p = 0.76) nor severe pneumonia (HR 1.03 (95%CI 0.73–1.44), p = 0.85) were associated with RASi therapy. (4) Conclusion: Our study showed no correlation between previous RASi treatment and death or severe COVID-19 pneumonia after adjustment for confounders.

Sign in / Sign up

Export Citation Format

Share Document