ACE2 (Angiotensin-Converting Enzyme 2) in Cardiopulmonary Diseases

Abstract

Discovery of ACE2 (angiotensin-converting enzyme 2) revealed that the renin-angiotensin system has 2 counterbalancing arms. ACE2 is a major player in the protective arm, highly expressed in lungs and gut with the ability to mitigate cardiopulmonary diseases such as inflammatory lung disease. ACE2 also exhibits activities involving gut microbiome, nutrition, and as a chaperone stabilizing the neutral amino acid transporter, B 0 AT1, in gut. But the current interest in ACE2 arises because it is the cell surface receptor for the novel coronavirus, severe acute respiratory syndrome coronavirus-2, to infect host cells, similar to severe acute respiratory syndrome coronavirus-2. This suggests that ACE2 be considered harmful, however, because of its important other roles, it is paradoxically a potential therapeutic target for cardiopulmonary diseases, including coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2. This review describes the discovery of ACE2, its physiological functions, and its place in the renin-angiotensin system. It illustrates new analyses of the structure of ACE2 that provides better understanding of its actions particularly in lung and gut, shedding of ACE2 by ADAM17 (a disintegrin and metallopeptidase domain 17 protein), and role of TMPRSS2 (transmembrane serine proteases 2) in severe acute respiratory syndrome coronavirus-2 entry into host cells. Cardiopulmonary diseases are associated with decreased ACE2 activity and the mitigation by increasing ACE2 activity along with its therapeutic relevance are addressed. Finally, the potential use of ACE2 as a treatment target in COVID-19, despite its role to allow viral entry into host cells, is suggested.

Angiotensin-converting enzyme 2 and COVID-19 in cardiorenal diseases

“…Imbalance between vasodeleterious AngII/AT1R signaling and beneficial Ang (1-7)/Mas receptor signaling has been shown to underlie multiple CVDs as well as pathophysiological states that predispose to CVD such as obesity, diabetes and kidney disease. This view is further supported by the evidence that catalytically active ACE2 treatment ameliorates CVDs in various experimental models of human diseases [ 1 , 2 , 12 , 15 ].…”

“…Thus, ACE2 regulates RAS directly by down-regulating AngII/AT1R signaling and indirectly by activating the counterregulatory Ang-(1-7)/Mas receptor axis. The vasodeleterious AngII/AT1R signaling induces vasoconstriction, profibrotic and proinflammatory effects, whereas Ang-(1-7)/Mas receptor signaling elicits vasodilatory, antiproliferative and antiapoptotic effects that are beneficial in various CVDs [ 1 , 5 , 13 , 14 ]. Imbalance between vasodeleterious AngII/AT1R signaling and beneficial Ang (1-7)/Mas receptor signaling has been shown to underlie multiple CVDs as well as pathophysiological states that predispose to CVD such as obesity, diabetes and kidney disease.…”

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“…Acute lung injury is the hallmark of COVID-19 and a subset of patients develop pneumonia and severe dyspnea requiring ICU admission. Most patients in critical condition have advanced age and pre-existing hypertension, cardiovascular disease (CVD), diabetes, obesity, and/or chronic lung conditions (Chen N. et al, 2020;Sharma et al, 2020b). Dyspnea and saturation of 90% or less despite oxygen supplementation is a major risk factor for fatal outcomes (Xie et al, 2020).…”

“…Actions of this axis are balanced by the vasoprotective axis of the RAS that includes ACE2, angiotensin-(1-7) and MAS). Protective effects of ACE2 against cardiorespiratory diseases have been explored for 20 years (Sharma et al, 2020b).…”

“…A randomized clinical trial evaluating efficacy, safety, and clinical impact of intravenous Ang-(1-7) vs. standard treatment in ICU patients with COVID-19 is underway (NCT04332666). Rationale for targeting the RAS to minimize systemic manifestations of COVID-19 are discussed in detail elsewhere (Sharma et al, 2020b).…”