Twenty years of progress in angiotensin converting enzyme 2 and its link to SARS-CoV-2 disease

Abstract

The virulence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the aggressive nature of the disease has transformed the universal pace of research in the desperate attempt to seek effective therapies to halt the morbidity and mortality of this pandemic. The rapid sequencing of the SARS-CoV-2 virus facilitated identification of the receptor for angiotensin converting enzyme 2 (ACE2) as the high affinity binding site that allows virus endocytosis. Parallel evidence that coronavirus disease 2019 (COVID-19) disease evolution shows greater lethality in patients with antecedent cardiovascular disease, diabetes, or even obesity questioned the potential unfavorable contribution of angiotensin converting enzyme (ACE) inhibitors or angiotensin II (Ang II) receptor blockers as facilitators of adverse outcomes due to the ability of these therapies to augment the transcription of Ace2 with consequent increase in protein formation and enzymatic activity. We review, here, the specific studies that support a role of these agents in altering the expression and activity of ACE2 and underscore that the robustness of the experimental data is associated with weak clinical long-term studies of the existence of a similar regulation of tissue or plasma ACE2 in human subjects.

The dual role of the immune system in the course of COVID-19. The fatal impact of the aging immune system

“…ACE – the dipeptidyl carboxypeptidase widely distributed in tissues – converts Ang I into Ang II, which by activation of its AT1 receptors is responsible for most pathophysiological effects of RAS. ACE2, an ACE homolog, is broadly expressed throughout the body, reaching high levels in epithelial cells of the nasal mucosa, salivary glands, lungs, kidneys and gastrointestinal tract as well as cardiomyocytes, adipocytes and endothelial cells [ 28 - 30 ]. Thus, the highest ACE2 expression was reported in the heart, kidneys, small intestine, testis, and lungs [ 31 ].…”

“…Thus, the highest ACE2 expression was reported in the heart, kidneys, small intestine, testis, and lungs [ 31 ]. Importantly in these tissues, ACE2 represents the main functional counterbalance to ACE as it (1) directly degrades Ang II and (2) is responsible for formation of angiotensin 1-7 [Ang-(1-7)], which by activation of MAS receptors exerts biological activities opposite to Ang II [ 27 , 28 , 32 , 33 ]. In 2003 ACE2 was found to be the main cellular virus entry receptor for SARS-CoV [ 34 ], and recently ACE2 was also established as the main receptor for SARS-CoV-2 [ 35 ].…”

ACE2, a multifunctional protein – from cardiovascular regulation to COVID-19

“…The consequences on the heart and kidney are reviewed by Sharma et al and Lores et al in this issue [18,19]. Ferrario et al discuss the role of the antiinflammatory effects of Ang-(1-7) and ACE2 in the pathogenesis of cardiovascular diseases [20]. In COVID-19, ACE2 activity is reduced compromising the protective RAS; and in this issue Steckelings and Sumners suggest this imbalance as a major pathogenetic factor for severe courses of the disease [21].…”

Renin-Angiotensin System Blockade Influences ACE2 in Human Type II Pneumocytes

“…10,11 The pressor arm of the RAS is implicated in the pathogenesis of acute lung injury; thus, the protective role of ACE2 results from Ang II downregulation and Ang-(1-7) upregulation. 10,11 Antihypertensive drugs targeting the pressor axis of the RAS such as ACE inhibitors (ACEIs) and type 1 Ang II receptor blockers (ARBs) are extensively used worldwide to treat many cardiovascular disorders. Evidence in rat kidney and heart showed that ACEIs and ARBs increase ACE2 gene transcripts.…”

“…6 ACE2 is primarily expressed in type II pneumocytes 4,[7][8][9] and protects against acute lung injury in several animal models of acute respiratory distress syndrome. 10,11 The pressor arm of the RAS is implicated in the pathogenesis of acute lung injury; thus, the protective role of ACE2 results from Ang II downregulation and Ang-(1-7) upregulation. 10,11 Antihypertensive drugs targeting the pressor axis of the RAS such as ACE inhibitors (ACEIs) and type 1 Ang II receptor blockers (ARBs) are extensively used worldwide to treat many cardiovascular disorders.…”