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 Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin–angiotensin system

2012 ◽  
Vol 216 (2) ◽  
pp. R1-R17 ◽  
Author(s):  
Robson A S Santos ◽  
Anderson J Ferreira ◽  
Thiago Verano-Braga ◽  
Michael Bader
Keyword(s):  
Renin Angiotensin System ◽  
Biologically Active ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Renin Angiotensin ◽  
Potential Interactions ◽  
G Protein Coupled

Angiotensin (Ang)-(1–7) is now recognized as a biologically active component of the renin–angiotensin system (RAS). Ang-(1–7) appears to play a central role in the RAS because it exerts a vast array of actions, many of them opposite to those attributed to the main effector peptide of the RAS, Ang II. The discovery of the Ang-converting enzyme (ACE) homolog ACE2 brought to light an important metabolic pathway responsible for Ang-(1–7) synthesis. This enzyme can form Ang-(1–7) from Ang II or less efficiently through hydrolysis of Ang I to Ang-(1–9) with subsequent Ang-(1–7) formation by ACE. In addition, it is now well established that the G protein-coupled receptor Mas is a functional binding site for Ang-(1–7). Thus, the axis formed by ACE2/Ang-(1–7)/Mas appears to represent an endogenous counterregulatory pathway within the RAS, the actions of which are in opposition to the vasoconstrictor/proliferative arm of the RAS consisting of ACE, Ang II, and AT1receptor. In this brief review, we will discuss recent findings related to the biological role of the ACE2/Ang-(1–7)/Mas arm in the cardiovascular and renal systems, as well as in metabolism. In addition, we will highlight the potential interactions of Ang-(1–7) and Mas with AT1and AT2receptors.

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 ACE2 Shedding and the Role in COVID-19

2022 ◽  
Vol 11 ◽  
Author(s):  
Jieqiong Wang ◽  
Huiying Zhao ◽  
Youzhong An
Keyword(s):  
Amino Acids ◽  
Viral Entry ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Underlying Mechanism ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Transmembrane Glycoprotein

Angiotensin converting enzyme 2 (ACE2), a transmembrane glycoprotein, is an important part of the renin-angiotensin system (RAS). In the COVID-19 epidemic, it was found to be the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). ACE2 maintains homeostasis by inhibiting the Ang II-AT1R axis and activating the Ang I (1-7)-MasR axis, protecting against lung, heart and kidney injury. In addition, ACE2 helps transport amino acids across the membrane. ACE2 sheds from the membrane, producing soluble ACE2 (sACE2). Previous studies have pointed out that sACE2 plays a role in the pathology of the disease, but the underlying mechanism is not yet clear. Recent studies have confirmed that sACE2 can also act as the receptor of SARS-COV-2, mediating viral entry into the cell and then spreading to the infective area. Elevated concentrations of sACE2 are more related to disease. Recombinant human ACE2, an exogenous soluble ACE2, can be used to supplement endogenous ACE2. It may represent a potent COVID-19 treatment in the future. However, the specific administration concentration needs to be further investigated.

scholarly journals Severe Acute Respiratory Syndrome Coronavirus 2, COVID-19, and the Renin-Angiotensin System

Hypertension ◽  
2020 ◽  
Vol 76 (5) ◽  
pp. 1350-1367 ◽  
Author(s):  
Matthew A. Sparks ◽  
Andrew M. South ◽  
Andrew D. Badley ◽  
Carissa M. Baker-Smith ◽  
Daniel Batlle ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Renin Angiotensin System ◽  
Organ Damage ◽  
Experimental Models ◽  
Multiple Organ ◽  
Host Cells ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Organ Systems

The coronavirus disease 2019 (COVID-19) pandemic is associated with significant morbidity and mortality throughout the world, predominantly due to lung and cardiovascular injury. The virus responsible for COVID-19—severe acute respiratory syndrome coronavirus 2—gains entry into host cells via ACE2 (angiotensin-converting enzyme 2). ACE2 is a primary enzyme within the key counter-regulatory pathway of the renin-angiotensin system (RAS), which acts to oppose the actions of Ang (angiotensin) II by generating Ang-(1–7) to reduce inflammation and fibrosis and mitigate end organ damage. As COVID-19 spans multiple organ systems linked to the cardiovascular system, it is imperative to understand clearly how severe acute respiratory syndrome coronavirus 2 may affect the multifaceted RAS. In addition, recognition of the role of ACE2 and the RAS in COVID-19 has renewed interest in its role in the pathophysiology of cardiovascular disease in general. We provide researchers with a framework of best practices in basic and clinical research to interrogate the RAS using appropriate methodology, especially those who are relatively new to the field. This is crucial, as there are many limitations inherent in investigating the RAS in experimental models and in humans. We discuss sound methodological approaches to quantifying enzyme content and activity (ACE, ACE2), peptides (Ang II, Ang-[1–7]), and receptors (types 1 and 2 Ang II receptors, Mas receptor). Our goal is to ensure appropriate research methodology for investigations of the RAS in patients with severe acute respiratory syndrome coronavirus 2 and COVID-19 to ensure optimal rigor and reproducibility and appropriate interpretation of results from these investigations.

scholarly journals Interactions of Renin-Angiotensin System and COVID-19: The Importance of Daily Rhythms in ACE2, ADAM17 and TMPRSS2 Expression

2021 ◽  
pp. S177-S194
Author(s):  
J ZLACKÁ ◽  
K STEBELOVÁ ◽  
M ZEMAN ◽  
I HERICHOVÁ
Keyword(s):  
Renin Angiotensin System ◽  
Positive Association ◽  
Ang Ii ◽  
Virus Envelope ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Renin Angiotensin ◽  
Circadian Control ◽  
A Disintegrin And Metalloproteinase

Angiotensin-converting enzyme 2 (ACE2) was identified as a molecule that mediates the cellular entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several membrane molecules of the host cell must cooperate in this process. While ACE2 serves in a membrane receptor-mediating interaction with the surface spike (S) glycoprotein of SARS-CoV-2 located on the virus envelope, enzyme A disintegrin and metalloproteinase 17 (ADAM17) regulates ACE2 availability on the membrane and transmembrane protease serine 2 (TMPRSS2) facilitates virus-cell membrane fusion. Interestingly, ACE2, ADAM17 and TMPRSS2 show a daily rhythm of expression in at least some mammalian tissue. The circadian system can also modulate COVID-19 progression via circadian control of the immune system (direct, as well as melatonin-mediated) and blood coagulation. Virus/ACE2 interaction causes ACE2 internalization into the cell, which is associated with suppressed activity of ACE2. As a major role of ACE2 is to form vasodilatory angiotensin 1-7 from angiotensin II (Ang II), suppressed ACE2 levels in the lung can contribute to secondary COVID-19 complications caused by up-regulated, pro-inflammatory vasoconstrictor Ang II. This is supported by the positive association of hypertension and negative COVID-19 prognosis although this relationship is dependent on numerous comorbidities. Hypertension treatment with inhibitors of renin-angiotensin system does not negatively influence prognosis of COVID-19 patients. It seems that tissue susceptibility to SARS-CoV-2 shows negative correlation to ACE2 expression. However, in lungs of infected patient, a high ACE2 expression is associated with better outcome, compared to low ACE2 expression. Manipulation of soluble ACE2 levels is a promising COVID-19 therapeutic strategy.

scholarly journals Quantifying Renin-Angiotensin-System Alterations in COVID-19

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2755
Author(s):  
Fabrizio Pucci ◽  
Filippo Annoni ◽  
Robson Augusto Souza dos Santos ◽  
Fabio Silvio Taccone ◽  
Marianne Rooman
Keyword(s):  
Meta Analysis ◽  
Renin Angiotensin System ◽  
Host Cells ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Renin Angiotensin ◽  
Physiological Processes ◽  
Open Questions ◽  
Clinical Investigations ◽  
Conflicting Evidence

The renin-angiotensin system (RAS) plays a pivotal role in a wide series of physiological processes, among which inflammation and blood pressure regulation. One of its key components, the angiotensin-converting enzyme 2, has been identified as the entry point of the SARS-CoV-2 virus into the host cells, and therefore a lot of research has been devoted to study RAS dysregulation in COVID-19. Here we discuss the alterations of the regulatory RAS axes due to SARS-CoV-2 infection on the basis of a series of recent clinical investigations and experimental analyzes quantifying, e.g., the levels and activity of RAS components. We performed a comprehensive meta-analysis of these data in view of disentangling the links between the impaired RAS functioning and the pathophysiological characteristics of COVID-19. We also review the effects of several RAS-targeting drugs and how they could potentially help restore the normal RAS functionality and minimize the COVID-19 severity. Finally, we discuss the conflicting evidence found in the literature and the open questions on RAS dysregulation in SARS-CoV-2 infection whose resolution would improve our understanding of COVID-19.

The Human-Covid Tango: Connecting the Dots

2020 ◽  
Author(s):  
Hamdi Hamdi ◽  
Ensaf Abdaldayem
Keyword(s):  
Coming Out ◽  
Renin Angiotensin System ◽  
The Elderly ◽  
Cardiovascular Complications ◽  
Scientific Activity ◽  
The Body ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Renin Angiotensin ◽  
Connecting The Dots

As the world grapples with a hot pandemic with various and expanding epicenters, a flurry of medical and scientific activity has gained speed and momentum in a race to halt Covid-19. Due to the urgency of the situation, publication peer review has been speeded up to get information published and turn the gears of research in search for a cure. A hot and controversial topic has been the connection between Covid-19 and the Renin-angiotensin system (RAS). Covid-19, like Sars before it, enters by way of the Angiotensin Converting Enzyme 2 (ACE2). ACE2 is ubiquitously expressed in many tissues in the body serving as the doorway by which the virus can enter and spread causing inflammatory havoc. Demographic evidence coming out of china and other locations make it clear that the elderly and those suffering cardiovascular complications such as hypertension etc are most at risk. The connection to RAS and the demographic nature of the data coming out has led many to advance hypothesis, recommendations and even therapies based on existing RAS inhibitors and other components of the renin-angiotensin system. It is pertinent to review the literature in the context of our understanding of the renin-angiotesnin system to allow better judgements to be made as well as lines of research initiated advancing a quick resolution to Covid-19.

scholarly journals The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1–7)

2018 ◽  
Vol 98 (1) ◽  
pp. 505-553 ◽  
Author(s):  
Robson Augusto Souza Santos ◽  
Walkyria Oliveira Sampaio ◽  
Andreia C. Alzamora ◽  
Daisy Motta-Santos ◽  
Natalia Alenina ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Renin Angiotensin System ◽  
The Body ◽  
Biologically Active ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
The Past ◽  
The Brain ◽  
System Focus

The renin-angiotensin system (RAS) is a key player in the control of the cardiovascular system and hydroelectrolyte balance, with an influence on organs and functions throughout the body. The classical view of this system saw it as a sequence of many enzymatic steps that culminate in the production of a single biologically active metabolite, the octapeptide angiotensin (ANG) II, by the angiotensin converting enzyme (ACE). The past two decades have revealed new functions for some of the intermediate products, beyond their roles as substrates along the classical route. They may be processed in alternative ways by enzymes such as the ACE homolog ACE2. One effect is to establish a second axis through ACE2/ANG-(1–7)/MAS, whose end point is the metabolite ANG-(1–7). ACE2 and other enzymes can form ANG-(1–7) directly or indirectly from either the decapeptide ANG I or from ANG II. In many cases, this second axis appears to counteract or modulate the effects of the classical axis. ANG-(1–7) itself acts on the receptor MAS to influence a range of mechanisms in the heart, kidney, brain, and other tissues. This review highlights the current knowledge about the roles of ANG-(1–7) in physiology and disease, with particular emphasis on the brain.

scholarly journals Angiotensin-(1-7)—A Potential Remedy for AKI: Insights Derived from the COVID-19 Pandemic

2021 ◽  
Vol 10 (6) ◽  
pp. 1200
Author(s):  
Samuel N. Heyman ◽  
Thomas Walther ◽  
Zaid Abassi
Keyword(s):  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Host Cells ◽  
Ang Ii ◽  
Viral Attachment ◽  
Beneficial Effects ◽  
Membrane Bound ◽  
G Protein Coupled ◽  
Parenchymal Damage

Membrane-bound angiotensin converting enzyme (ACE) 2 serves as a receptor for the Sars-CoV-2 spike protein, permitting viral attachment to target host cells. The COVID-19 pandemic brought into light ACE2, its principal product angiotensin (Ang) 1-7, and the G protein-coupled receptor for the heptapeptide (MasR), which together form a still under-recognized arm of the renin–angiotensin system (RAS). This axis counteracts vasoconstriction, inflammation and fibrosis, generated by the more familiar deleterious arm of RAS, including ACE, Ang II and the ang II type 1 receptor (AT1R). The COVID-19 disease is characterized by the depletion of ACE2 and Ang-(1-7), conceivably playing a central role in the devastating cytokine storm that characterizes this disorder. ACE2 repletion and the administration of Ang-(1-7) constitute the therapeutic options currently tested in the management of severe COVID-19 disease cases. Based on their beneficial effects, both ACE2 and Ang-(1-7) have also been suggested to slow the progression of experimental diabetic and hypertensive chronic kidney disease (CKD). Herein, we report a further step undertaken recently, utilizing this type of intervention in the management of evolving acute kidney injury (AKI), with the expectation of renal vasodilation and the attenuation of oxidative stress, inflammation, renal parenchymal damage and subsequent fibrosis. Most outcomes indicate that triggering the ACE2/Ang-(1-7)/MasR axis may be renoprotective in the setup of AKI. Yet, there is contradicting evidence that under certain conditions it may accelerate renal damage in CKD and AKI. The nature of these conflicting outcomes requires further elucidation.

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