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Insights on SARS-CoV-2 Molecular Interactions With the Renin-Angiotensin System

The emergence of SARS-CoV-2/human/Wuhan/X1/2019, a virus belonging to the species Severe acute respiratory syndrome-related coronavirus, and the recognition of Coronavirus Disease 2019 (COVID-19) as a pandemic have highly increased the scientific research regarding the pathogenesis of COVID-19. The...

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Autores principales: Costa, Larissa Braga, Perez, Lucas Giandoni, Palmeira, Vitória Andrade, Macedo e Cordeiro, Thiago, Ribeiro, Victor Teatini, Lanza, Katharina, Simões e Silva, Ana Cristina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525006/
https://www.ncbi.nlm.nih.gov/pubmed/33042994
http://dx.doi.org/10.3389/fcell.2020.559841
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author Costa, Larissa Braga
Perez, Lucas Giandoni
Palmeira, Vitória Andrade
Macedo e Cordeiro, Thiago
Ribeiro, Victor Teatini
Lanza, Katharina
Simões e Silva, Ana Cristina
author_facet Costa, Larissa Braga
Perez, Lucas Giandoni
Palmeira, Vitória Andrade
Macedo e Cordeiro, Thiago
Ribeiro, Victor Teatini
Lanza, Katharina
Simões e Silva, Ana Cristina
author_sort Costa, Larissa Braga
collection PubMed
description The emergence of SARS-CoV-2/human/Wuhan/X1/2019, a virus belonging to the species Severe acute respiratory syndrome-related coronavirus, and the recognition of Coronavirus Disease 2019 (COVID-19) as a pandemic have highly increased the scientific research regarding the pathogenesis of COVID-19. The Renin Angiotensin System (RAS) seems to be involved in COVID-19 natural course, since studies suggest the membrane-bound Angiotensin-converting enzyme 2 (ACE2) works as SARS-CoV-2 cellular receptor. Besides the efforts of the scientific community to understand the virus’ molecular interactions with human cells, few studies summarize what has been so far discovered about SARS-CoV-2 signaling mechanisms and its interactions with RAS molecules. This review aims to discuss possible SARS-CoV-2 intracellular signaling pathways, cell entry mechanism and the possible consequences of the interaction with RAS components, including Angiotensin II (Ang II), Angiotensin-(1-7) [Ang-(1-7)], Angiotensin-converting enzyme (ACE), ACE2, Angiotensin II receptor type-1 (AT1), and Mas Receptor. We also discuss ongoing clinical trials and treatment based on RAS cascade intervention. Data were obtained independently by the two authors who carried out a search in the PubMed, Embase, LILACS, Cochrane, Scopus, SciELO and the National Institute of Health databases using Medical Subject Heading terms as “SARS-CoV-2,” “COVID-19,” “Renin Angiotensin System,” “ACE2,” “Angiotensin II,” “Angiotensin-(1-7),” and “AT1 receptor.” Similarly to other members of Coronaviridae family, the molecular interactions between the pathogen and the membrane-bound ACE2 are based on the cleavage of the spike glycoprotein (S) in two subunits. Following the binding of the S1 receptor-binding domain (RBD) to ACE2, transmembrane protease/serine subfamily 2 (TMPRSS2) cleaves the S2 domain to facilitate membrane fusion. It is very likely that SARS-CoV-2 cell entry results in downregulation of membrane-bound ACE2, an enzyme that converts Ang II into Ang-(1-7). This mechanism can result in lung injury and vasoconstriction. In addition, Ang II activates pro-inflammatory cascades when binding to the AT1 Receptor. On the other hand, Ang-(1-7) promotes anti-inflammatory effects through its interactions with the Mas Receptor. These molecules might be possible therapeutic targets for treating COVID-19. Thus, the understanding of SARS-CoV-2 intracellular pathways and interactions with the RAS may clarify COVID-19 physiopathology and open perspectives for new treatments and strategies.
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spelling pubmed-75250062020-10-09 Insights on SARS-CoV-2 Molecular Interactions With the Renin-Angiotensin System Costa, Larissa Braga Perez, Lucas Giandoni Palmeira, Vitória Andrade Macedo e Cordeiro, Thiago Ribeiro, Victor Teatini Lanza, Katharina Simões e Silva, Ana Cristina Front Cell Dev Biol Cell and Developmental Biology The emergence of SARS-CoV-2/human/Wuhan/X1/2019, a virus belonging to the species Severe acute respiratory syndrome-related coronavirus, and the recognition of Coronavirus Disease 2019 (COVID-19) as a pandemic have highly increased the scientific research regarding the pathogenesis of COVID-19. The Renin Angiotensin System (RAS) seems to be involved in COVID-19 natural course, since studies suggest the membrane-bound Angiotensin-converting enzyme 2 (ACE2) works as SARS-CoV-2 cellular receptor. Besides the efforts of the scientific community to understand the virus’ molecular interactions with human cells, few studies summarize what has been so far discovered about SARS-CoV-2 signaling mechanisms and its interactions with RAS molecules. This review aims to discuss possible SARS-CoV-2 intracellular signaling pathways, cell entry mechanism and the possible consequences of the interaction with RAS components, including Angiotensin II (Ang II), Angiotensin-(1-7) [Ang-(1-7)], Angiotensin-converting enzyme (ACE), ACE2, Angiotensin II receptor type-1 (AT1), and Mas Receptor. We also discuss ongoing clinical trials and treatment based on RAS cascade intervention. Data were obtained independently by the two authors who carried out a search in the PubMed, Embase, LILACS, Cochrane, Scopus, SciELO and the National Institute of Health databases using Medical Subject Heading terms as “SARS-CoV-2,” “COVID-19,” “Renin Angiotensin System,” “ACE2,” “Angiotensin II,” “Angiotensin-(1-7),” and “AT1 receptor.” Similarly to other members of Coronaviridae family, the molecular interactions between the pathogen and the membrane-bound ACE2 are based on the cleavage of the spike glycoprotein (S) in two subunits. Following the binding of the S1 receptor-binding domain (RBD) to ACE2, transmembrane protease/serine subfamily 2 (TMPRSS2) cleaves the S2 domain to facilitate membrane fusion. It is very likely that SARS-CoV-2 cell entry results in downregulation of membrane-bound ACE2, an enzyme that converts Ang II into Ang-(1-7). This mechanism can result in lung injury and vasoconstriction. In addition, Ang II activates pro-inflammatory cascades when binding to the AT1 Receptor. On the other hand, Ang-(1-7) promotes anti-inflammatory effects through its interactions with the Mas Receptor. These molecules might be possible therapeutic targets for treating COVID-19. Thus, the understanding of SARS-CoV-2 intracellular pathways and interactions with the RAS may clarify COVID-19 physiopathology and open perspectives for new treatments and strategies. Frontiers Media S.A. 2020-09-16 /pmc/articles/PMC7525006/ /pubmed/33042994 http://dx.doi.org/10.3389/fcell.2020.559841 Text en Copyright © 2020 Costa, Perez, Palmeira, Macedo e Cordeiro, Ribeiro, Lanza and Simões e Silva. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Costa, Larissa Braga
Perez, Lucas Giandoni
Palmeira, Vitória Andrade
Macedo e Cordeiro, Thiago
Ribeiro, Victor Teatini
Lanza, Katharina
Simões e Silva, Ana Cristina
Insights on SARS-CoV-2 Molecular Interactions With the Renin-Angiotensin System
title Insights on SARS-CoV-2 Molecular Interactions With the Renin-Angiotensin System
title_full Insights on SARS-CoV-2 Molecular Interactions With the Renin-Angiotensin System
title_fullStr Insights on SARS-CoV-2 Molecular Interactions With the Renin-Angiotensin System
title_full_unstemmed Insights on SARS-CoV-2 Molecular Interactions With the Renin-Angiotensin System
title_short Insights on SARS-CoV-2 Molecular Interactions With the Renin-Angiotensin System
title_sort insights on sars-cov-2 molecular interactions with the renin-angiotensin system
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525006/
https://www.ncbi.nlm.nih.gov/pubmed/33042994
http://dx.doi.org/10.3389/fcell.2020.559841
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