Which ones, when and why should renin-angiotensin system inhibitors work against COVID-19?

Abstract

The article describes the possible pathophysiological origin of COVID-19 and the crucial role of renin-angiotensin system (RAS), providing several “converging” evidence in support of this hypothesis. SARS-CoV-2 has been shown to initially upregulate ACE2 systemic activity (early phase), which can subsequently induce compensatory responses leading to upregulation of both arms of the RAS (late phase) and consequently to critical, advanced and untreatable stages of COVID-19 disease. The main and initial actors of the process are ACE2 and ADAM17 zinc-metalloproteases, which, initially triggered by SARS-CoV-2 spike proteins, work together in increasing circulating Ang 1–7 and Ang 1–9 peptides and downstream (Mas and Angiotensin type 2 receptors) pathways with anti-inflammatory, hypotensive and antithrombotic activities. During the late phase of severe COVID-19, compensatory secretion of renin and ACE enzymes are subsequently upregulated, leading to inflammation, hypertension and thrombosis, which further sustain ACE2 and ADAM17 upregulation. Based on this hypothesis, COVID-19-phase-specific inhibition of different RAS enzymes is proposed as a pharmacological strategy against COVID-19 and vaccine-induced adverse effects. The aim is to prevent the establishment of positive feedback-loops, which can sustain hyperactivity of both arms of the RAS independently of viral trigger and, in some cases, may lead to Long-COVID syndrome.

Circulating ACE2 activity predicts mortality and disease severity in hospitalized COVID-19 patients

“…Normally, circulating level of ACE2 is low (< 17 mU/L)(Úri et al 2016(Úri et al , Fagyas et al 2021), but becomes elevated in various cardiovascular disorders, such as hypertension(Úri et al 2016), aortic stenosis(Fagyas et al 2021), heart failure(Fagyas et al 2021) and atrial fibrillation(Wallentin et al 2020). These data suggest that elevated baseline ACE2 in the circulation may predispose to severe COVID-19, and SARS-CoV-2 infection can further increase ACE2 activity(Montanari et al 2021). Despite these facts, controversial results on ACE2 level and activity have recently been published in different cohorts of COVID-19 patients ranging from (highly) elevated(Nagy et al 2021, van Lier et al 2021, Kragstrup et al 2021, Kaur et al 2021, Patel et al 2021, Reindl-Schwaighofer et al 2021 to unchanged(Rieder et al 2020, Kintscher et al.…”

Quantifying Renin-Angiotensin-System Alterations in COVID-19

“…Its overexpression has been related to several pathophysiological conditions that range from vascular dysfunctions to pulmonary disease and cancer [59,60]. In COVID-19, the upregulated activity of ADAM17 increases ACE2 shedding, which in turn leads to higher sACE2 levels [61], and to the increase of TNF-α production. In a kind of positive feedback loop, the ADAM17-mediated shedding activity appears to be enhanced by the binding of the viral spike protein to ACE2 [23,62,63], and to be stimulated by AngII [42] and the pro-inflammatory cytokines interleukin (IL)-1β and TNF-α [64], whose secretion is elevated in COVID-19 patients.…”

“…At first sight, normal RAS functioning could be restored in this scenario by acting against the peak of ACE2 activity. Indeed, inhibiting ACE2 or the metalloprotease ADAM17 that is responsible for ACE2 shedding could be an effective way to block the overactivation of the RAS axes, which in turn would lead to the suppression of the inflammatory responses in COVID-19 and attenuate severe lung injury [61,120]. Some studies propose the introduction of ACE2 inhibitor drugs [57].…”

Hypothesis: Efficacy of early treatments with some NSAIDs in COVID‐19: Might it also depend on their direct and/or indirect zinc chelating ability?

“…Unlike HCoV‐NL63, SARS‐CoV binding to cell surface ACE2 has been shown to induce both ADAM17‐mediated shedding of an enzymatically active ACE2 and severe acute respiratory syndrome (SARS) (Glowacka et al, 2010 ; Haga et al, 2008 ; Lambert et al, 2005 ; Lartey et al, 2022 ; Yeung et al, 2021 ), raising the possibility that systemic ACE2 hyperactivity may participate in COVID‐19 pathogenesis (Montanari et al, 2021 ; Zamai, 2020 , 2021 ; Zanza et al, 2021 ). As a consequence of SARS‐CoV spike binding, ACE2 expressed on endothelial cells would be down‐modulated and an excess of active ACE2 released in circulation (Fagyas et al, 2022 ; Montanari et al, 2021 ; Zamai, 2020 ).…”

“…Unlike HCoV‐NL63, SARS‐CoV binding to cell surface ACE2 has been shown to induce both ADAM17‐mediated shedding of an enzymatically active ACE2 and severe acute respiratory syndrome (SARS) (Glowacka et al, 2010 ; Haga et al, 2008 ; Lambert et al, 2005 ; Lartey et al, 2022 ; Yeung et al, 2021 ), raising the possibility that systemic ACE2 hyperactivity may participate in COVID‐19 pathogenesis (Montanari et al, 2021 ; Zamai, 2020 , 2021 ; Zanza et al, 2021 ). As a consequence of SARS‐CoV spike binding, ACE2 expressed on endothelial cells would be down‐modulated and an excess of active ACE2 released in circulation (Fagyas et al, 2022 ; Montanari et al, 2021 ; Zamai, 2020 ). Indeed, spike protein alone as well as the SARS‐CoV viral infection have been shown to both down‐modulate ACE2 surface expression and damage endothelium in in vivo animal models (Lei et al, 2021 ; Nuovo et al, 2021 ), suggesting that the renin–angiotensin system dysregulation induced by SARS‐CoV spike binding independently of viral infection may play a central role in COVID‐19.…”