The interaction of RAAS inhibitors with COVID-19: Current progress, perspective and future

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently defined as the worst pandemic disease. SARS-CoV-2 infects human cells via the binding of its S protein to the receptor angiotensin-converting enzyme (ACE2). The use of ACEIs/ARBs (RAAS inhibitors) regulates the renin-angiotensin-aldosterone system (RAAS) and may increase ACE2 expression. Considering the large use of ACEIs/ARBs in hypertensive patients, some professional groups are concerned about whether the use of RAAS inhibitors affects the risk of SARS-CoV-2 infection or the risk of severe illness and mortality in COVID-19 patients. In this review, we summarize preclinical and clinical studies to investigate whether the use of ACEIs/ARBs increases ACE2 expression in animals or patients. We also analyzed whether the use of these drugs affects the risk of SARS-CoV-2 infection, severe illness or mortality based on recent studies. Finally, the review suggests that current evidence does not support the concerns.

Keywords: ACE2; COVID-19; RAAS inhibitor; SARS-CoV-2.

Graphical abstract

Fig. 1

Interaction between SARS-CoV-2 and the renin–angiotensin–aldosterone system. ACE metabolizes Ang I to generate Ang II, which mainly binds AT1R to activate the system and result in lung injury. ACE2 could metabolizes Ang II to generate Ang 1–7 and convert Ang I to Ang 1–9. Ang 1–9 is furtherly metabolized to generate Ang 1–7. Ang 1–7 exerts the protective effect on lung injury via binding the receptor MasR. AT2R also has a beneficial effect. The activation of AT1R promotes ADAM17 (as a “sheddase”) to cleave the extracellular domain of surface ACE2, generating sACE2 and reducing surface ACE2 expression. Recombinant sACE2 may be a treatment for SARS-CoV-2. After processing of the S-protein by TMPRSS2, SARS-CoV-2 performs its human-cell entry via binding its S-protein to ACE2 and the RBD of S-protein is responsible for the process. After endocytosis of the viral complex, surface ACE2 is further down-regulated, resulting in unopposed Ang II accumulation. Local activation of the renin–angiotensin–aldosterone system may regulate lung injury responses to viral insults. The virus replicates inside the cell, leading to pneumonia and even inflammatory cytokine storms, which may contribute to other organ injury. Abbreviation: ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; ADAM17, a disintegrin and metalloprotease 17; Ang, angiotensin; AT1R, Ang II type 1 receptor; AT2R, Ang II type 2 receptor; ACEI, ACE inhibitor; ARB, angiotensin receptor blocker; MasR, Mas receptor; TMPRSS2, type II transmembrane serine protease.

Fig. 2

The use of ACEI/ARB, ACE2 expression levels in animals or patients, the risk of SARS-CoV-2 infection, severe cases or mortality. The use of ACEI/ARB increases ACE2 expression or activity in animals: lack consistent evidence. The use of ACEI/ARB increases ACE2 expression or activity in patients: no enough evidence. The use of ACEI/ARB increases the risk of SARS-CoV-2 infection: no evidence. The use of ACEI/ARB increases the risk of severe illness or mortality in COVID-19 patients: no evidence. Whether the use of ACEI/ARB has beneficial or harmful effect on the treatment or prognosis of COVID-19 is still unknown, which need one or more randomized trials to answer the question.