Abstract
Angiotensin-converting enzyme 2 (ACE2) protects against organ damage in hypertension and cardiovascular diseases by counter regulating the renin-angiotensin system (RAS). ACE2 is also the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on the claim that RAS inhibitors (RASIs) cause ACE2 overexpression in some animal experiments, concerns have arisen that RASIs may aggravate SARS-CoV-2 infection and coronavirus disease-2019 severity in RASI-treated patients. To achieve a comprehensive review, a systematic search of MEDLINE/PubMed was conducted regarding the effects of RASIs on tissue ACE2 mRNA/protein expression in healthy animals and animal models of human diseases. We identified 88 eligible articles involving 168 experiments in the heart, kidneys, lungs, and other organs. Three of 38 experiments involving healthy animals showed ACE2 expression greater than twice that of the control (overexpression). Among 102 disease models (130 experiments), baseline ACE2 was overexpressed in 16 models (18 experiments) and less than half the control level (repression) in 28 models (40 experiments). In 72 experiments, RASIs did not change ACE2 levels from the baseline levels of disease models. RASIs caused ACE2 overexpression compared to control levels in seven experiments, some of which were unsupported by other experiments under similar conditions. In 36 experiments, RASIs reversed or prevented disease-induced ACE2 repression, yielding no or marginal changes. Therefore, ACE2 overexpression appears to be a rare rather than common consequence of RASI treatment in healthy animals and disease models. Future studies should clarify the pathophysiological significance of RASI-induced reversal or prevention of ACE2 repression in disease models.
Highlights
Angiotensin-converting enzyme 2 (ACE2) is a membranebound carboxydipeptidase that converts angiotensin (Ang) I into Ang1-9 and AngII into Ang1-7 [1, 2]
Previous reviews have tended to focus on renin-angiotensin system (RAS) inhibitor (RASI)-induced ACE2 expression changes compared to the baseline levels of disease models [2, 5,6,7,8]
Most articles included in this analysis aimed to investigate whether ACE2 is associated with the organ-protective mechanisms of RASIs
Summary
Angiotensin-converting enzyme 2 (ACE2) is a membranebound carboxydipeptidase that converts angiotensin (Ang) I into Ang and AngII into Ang1-7 [1, 2]. This is truly at the crux of a current problem and its associated confusion, in that ACE2 has been identified as the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19) [10,11,12] This finding raised concerns that ARBs and ACEIs may augment susceptibility to SARS-CoV-2 infection and aggravate the severity of COVID-19 in hypertensive or CVD patients receiving these drugs [7, 8]. Previous reviews have tended to focus on RAS inhibitor (RASI)-induced ACE2 expression changes compared to the baseline levels of disease models [2, 5,6,7,8] Such comparisons may lead to overestimation of RASI-induced ACE2 overexpression beyond the levels in healthy or control animals. Expression changes were semiquantitatively graded as follows: overexpression, when the ACE2 expression level was greater than twice that in the control group; repression, when the ACE2 expression level was less than half that in the control group; and no/ marginal change, when the ACE2 expression remained at a level from half to twice that of the control group
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