ACE2, the Counter-Regulatory Renin–Angiotensin System Axis and COVID-19 Severity

Abstract

Angiotensin (ANG)-converting enzyme (ACE2) is an entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). ACE2 also contributes to a deviation of the lung renin–angiotensin system (RAS) towards its counter-regulatory axis, thus transforming harmful ANG II to protective ANG (1–7). Based on this purported ACE2 double function, it has been put forward that the benefit from ACE2 upregulation with renin–angiotensin–aldosterone system inhibitors (RAASi) counterbalances COVID-19 risks due to counter-regulatory RAS axis amplification. In this manuscript we discuss the relationship between ACE2 expression and function in the lungs and other organs and COVID-19 severity. Recent data suggested that the involvement of ACE2 in the lung counter-regulatory RAS axis is limited. In this setting, an augmentation of ACE2 expression and/or a dissociation of ACE2 from the ANG (1–7)/Mas pathways that leaves unopposed the ACE2 function, the SARS-CoV-2 entry receptor, predisposes to more severe disease and it appears to often occur in the relevant risk factors. Further, the effect of RAASi on ACE2 expression and on COVID-19 severity and the overall clinical implications are discussed.

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“…The physiological role of ACE2 is to regulate blood pressure. ACE2 transforms harmful vasoconstrictor angiotensin II to protective angiotensin 1–7, which are vasodilators [ 27 ]. In the autopsy of patients who died of ARDS, only high levels of pro-inflammatory cytokines were detected in ACE2 + cells infected with SARS-CoV [ 28 ].…”

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“…After the first detection in Wuhan, China, it quickly spread worldwide and was declared a pandemic by the World Health Organization (WHO) [1] , [2] , [3] , [4] , [5] . The entry of the SARS-CoV-2 into the host cell is through its binding to the angiotensin-converting enzyme 2 (ACE2), similar to previous coronavirus SARS-CoV [5] , [6] , [7] , [8] , [9] . ACE2 and its angiotensin-converting enzyme (ACE) homologue perform as a significant component of the renin-angiotensin-aldosterone system (RAAS), a dynamic system in vascular function, blood pressure, and immune response regulation.…”

“…Initially, higher ACE2 protein levels were considered the main cause of the susceptibility to SARS-CoV-2 infection [5] , [8] , [10] . However, conflicting data show that patients with COVID-19 complications also had an increased pro-inflammatory profile and reduced ACE2 baseline levels associated with upregulating of Ang II and downregulation of Ang-(1-7) levels [7] , [8] .…”

“…Initially, higher ACE2 protein levels were considered the main cause of the susceptibility to SARS-CoV-2 infection [5] , [8] , [10] . However, conflicting data show that patients with COVID-19 complications also had an increased pro-inflammatory profile and reduced ACE2 baseline levels associated with upregulating of Ang II and downregulation of Ang-(1-7) levels [7] , [8] . Among the available hypotheses, it is thought that people in the risk group have an imbalance between ACE and ACE2 activity that leads to pro-inflammatory responses, predisposing them to cytokine storm syndrome [8] .…”

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“…With respect to anti-hypertensive treatment, the role of ACE-inhibitors has been extensively sought during the pandemic, since the aminopeptidase angiotensin-converting enzyme 2 (ACE2) has been identified as a receptor for SARS-CoV2, due to its binding to the spike protein of the virus. The review by Triposkiadis et al [7], included in this issue, elucidates the role of ACE2 in COVID-19 progression and severity, reassuring the scientific community on the safety of continuing the use of ACE inhibitors.…”