ACE2: The key Molecule for Understanding the Pathophysiology of Severe and Critical Conditions of COVID-19: Demon or Angel?

Abstract

Recently, the SARS-CoV-2 induced disease COVID-19 has spread all over the world. Nearly 20% of the patients have severe or critical conditions. SARS-CoV-2 exploits ACE2 for host cell entry. ACE2 plays an essential role in the renin-angiotensin-aldosterone system (RAAS), which regulates blood pressure and fluid balance. ACE2 also protects organs from inflammatory injuries and regulates intestinal functions. ACE2 can be shed by two proteases, ADAM17 and TMPRSS2. TMPRSS2-cleaved ACE2 allows SARS-CoV-2 cell entry, whereas ADAM17-cleaved ACE2 offers protection to organs. SARS-CoV-2 infection-caused ACE2 dysfunction worsens COVID-19 and could initiate multi-organ failure. Here, we will explain the role of ACE2 in the pathogenesis of severe and critical conditions of COVID-19 and discuss auspicious strategies for controlling the disease.Viruses 2020, 12, 491 2 of 10 Profile of ACE2Human angiotensin-converting enzyme-related carboxypeptidase ACE2 is encoded by the ACE2 gene which maps to chromosome Xp22 [6]. ACE2 is a type I transmembrane protein, comprised of an extracellular heavily N-glycosylated N-terminal domain containing the carboxypeptidase site and a short intracellular C-terminal cytoplasmic tail [7]. The N-terminal peptidase domain is also the SARS-CoV binding site [8]. There are two forms of ACE2 protein: cellular (membrane-bound) form and circulating (soluble) form. Cellular ACE2 protein is the full-length protein which is expressed abundantly in pneumocytes and enterocytes of the small intestine [9]. ACE2 is also expressed in vascular endothelial cells of the heart, the kidneys, and other organs, such as the brain. However, ACE2 is absent in the spleen, thymus, lymph nodes, bone marrow, and cells of the immune system (including B and T lymphocytes, and macrophages) [10,11].Circulating ACE2 (with the N-terminal peptidase domain) is cleaved from the full-length ACE2 on the cell membrane by the metalloprotease ADAM17 and then released into the extracellular environment [7]. The type II transmembrane serine protease, TMPRSS2 was found to compete with ADAM17 for ACE2 shedding but cleaves ACE2 differently. Both ADAM17 and TMPRSS2 remove a short C-terminal fragment from ACE2. Arginine and lysine residues within amino acids 652 to 659 are critical for ADAM17 shedding, whereas arginine and lysine residues within amino acids 697 to 716 are essential for TMPRSS2 shedding. Only cleavage by TMPRSS2 results in augmented SARS-CoV cell entry [12][13][14][15]. There are two ways for SARS-CoV to enter the target cell: endocytosis, and fusion of the viral membrane with a membrane of the target cell, which is 100 times more efficient than endocytosis for viral replication [16]. With the help of TMPRSS2, ADAM17-regulated ectodomain shedding of ACE2 could induce SARS-CoV cell entry through endocytosis [7,12]; however, ADAM17 activity is not required for SARS-CoV cell entry through fusion [12]. As the N-terminal domain is the coronavirus binding site, circulating ACE2 also binds to the virus. Iwata-Yoshikawa et al. infected both ...

Fisiopatologia da trombose associada à infecção pelo SARS-CoV-2

“…2 ACE2 acts as a membrane receptor in this process, which also involves interactions with other effectors, such as type 2 transmembrane serine proteases. 3 The ACE2 protein plays an important role as a negative effector in the renin angiotensin aldosterone system, converting angiotensins I and II into angiotensins 1-9 and 1-7, respectively. Angiotensins 1-9 and 1-7 have vasodilatory and anti-inflammatory effects, among other actions, thereby antagonizing the classic hypertensive and inflammatory effects of angiotensin II.…”

“…Angiotensins 1-9 and 1-7 have vasodilatory and anti-inflammatory effects, among other actions, thereby antagonizing the classic hypertensive and inflammatory effects of angiotensin II. 2,3 Infection by SARS-CoV-2 causes death of cells rich in ACE2 receptors and cellular internalization of a proportion of these receptors, ultimately causing a reduction in circulating ACE2 activity. 4 This results in angiotensin II activity predominating over activity of angiotensins 1-7 and 1-9.…”

A computational and bioinformatic analysis of ACE2: an elucidation of its dual role in COVID-19 pathology and finding its associated partners as potential therapeutic targets

“…Consequently, ACE2 serves as a double‐edged sword playing dual roles of a demon as well as an angel. It not only opens the doors for SARS-CoV-2 as a receptor but also helps protects the body from severe pathological changes (Cheng, Wang et al 2020 ; Xiao, Sakagami et al 2020 ; Yan, Xiao et al 2020 ). In the current COVID-19 outbreak, ACE2 is a topic of pronounced interest and several studies are being carried out to assess the interaction of SARS-CoV-2 with ACE2, the receptor.…”

Chloroquine and hydroxychloroquine as ACE2 blockers to inhibit viropexis of 2019-nCoV Spike pseudotyped virus

“…conducted a molecular docking experiment between CQ and ACE2 and found that CQ binds to ACE2 with low binding energy and forms a stable complex system (Abdelli et al, 2020). Studies have shown that ACE2 is a type I membrane-bound glycoprotein composed of 805 amino acids, mainly distributed in vascular endothelial cells, alveolar and renal tubular epithelial cells, and profoundly expressed in tissues such as heart, kidney, retina, and gastrointestinal tissue (Xiao et al, 2020). Flow cytometry and immunoprecipitation studies have shown that during alveolar epithelial cell infection with SARS virus, CQ and HCQ can prevent the binding of viral S protein to ACE2 by disrupting ACE2 terminal glycosylation (Brufsky, 2020;Vincent et al, 2005).…”