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

Abstract

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

Obesity as a Risk Factor for Severe COVID-19 and Complications: A Review

“…Binding of SARS-CoV-2 to ACE2, which prevents ACE2 from exerting its enzymatic activities [ 60 ], has further consequences for immune system functioning. Decreased enzymatic ACE2 activity results in a reduction of anti-inflammatory Ang-1-7 and an accumulation of pro-inflammatory Ang-II.…”

COVID-19 and Hypertension: The What, the Why, and the How

“…Besides, hypertension is associated with endothelial dysfunction and a pro-inflammatory state, which includes higher levels of Ang II, chemokines, and cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) ( de Miguel et al, 2015 ). Therefore, RAS imbalance that favors the pro-inflammatory state is proposed to be the center of COVID-19 pathophysiological mechanisms ( Costa et al, 2020 ).…”

“…Consequently, Ang 1-7 decreases and this lessens the protective effects of the non-conventional ACE2/Ang 1-7/Mas axis. Since Ang II has pro-oxidative and pro-inflammatory actions, excessive Ang II promotes endothelial dysfunction and cytokine storm that subsequently led to the pulmonary, inflammatory, and hematological complications of COVID-19 ( Costa et al, 2020 ; Vieira et al, 2021 ).…”

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“…SARS-CoV-2 uses ACE2 as a functional receptor to infect human epithelial cells [19] . In particular, the receptor-binding domain (RBD) of the S1 subunit of the spike protein directly binds to the peptidase domain (PD) of ACE2 [20] , [21] , [22] .…”