Angiotensin-converting enzyme 2 (ACE2)[5] is anenzyme that can be found either attached to themembrane of cells (mACE2) in theintestines,kidney,testis,gallbladder, andheart or in a soluble form (sACE2).[6][7][8] Both membrane bound and soluble ACE2 are integral parts of therenin–angiotensin–aldosterone system (RAAS) that exists to keep the body's blood pressure in check. mACE2 is cleaved by the enzyme ADAM17 in a process regulated bysubstrate presentation. ADAM17 cleavage releases the extracellular domain creating soluble ACE2 (sACE2).[9] ACE2 enzyme activity opposes the classical arm of the RAAS by lowering blood pressure through catalyzing thehydrolysis ofangiotensin II (avasoconstrictorpeptide which raises blood pressure) intoangiotensin (1–7) (avasodilator).[8][10][11] Angiotensin (1-7) in turns binds to MasR receptors creating localized vasodilation and hence decreasing blood pressure.[12] This decrease in blood pressure makes the entire process a promising drug target for treatingcardiovascular diseases.[13][14]
mACE2 is a single-passtype I membrane protein, with its enzymatically activedomain exposed on the surface of cells in the intestines and other tissues.[6][7] The extracellular domain of mACE2 can becleaved from thetransmembrane domain by another enzyme known asADAM17 a member of thesheddase enzyme family, during the protective phase ofRAAS, the Renin–Angiotensin–Aldosterone System, which regulates our body's blood pressure. The resulting cleaved protein is known as soluble ACE2 or sACE2. It is released into the bloodstream where one of sACE2's functions is to turn excess angiotensin II into angiotensin 1-7 which binds to MasR receptors creating localized vasodilation and hence decreasing blood pressure. Excess sACE2 may ultimately be excreted in the urine.[18][19]
As part of the renin–angiotensin–aldosterone system (RAAS) protective phase, soluble ACE2's (sACE2) important function is to act as a counterbalance to theangiotensin-converting enzyme (ACE). ACE cleavesangiotensin I hormone into the vasoconstrictingangiotensin II which causes a cascade of hormonal reactions which is part of the body's harmful phase of RAAS, which ultimately leads to an increase in the body's blood pressure. ACE2 has an opposing effect to ACE, degrading angiotensin II intoangiotensin (1-7), thereby lowering blood pressure.[22][23]
sACE2, as part of RAAS's protective phase, cleaves the carboxyl-terminal amino acid phenylalanine from angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) and hydrolyses it into the vasodilatorangiotensin (1-7) (H-Asp-Arg-Val-Tyr-Ile-His-Pro-OH), which binds to Mas Receptors and ultimately leads to a decrease in blood pressure.[24][17] sACE2 can also cleave numerous peptides, including[des-Arg9]-bradykinin,apelin,neurotensin,dynorphin A, andghrelin.[17]
mACE2 also regulates the membrane trafficking of the neutral amino acid transporterSLC6A19 and has been implicated inHartnup's disease.[25][26][27]
Research in mice has shown that ACE2 (whether it is the membrane bound version or soluble is inconclusive) is involved in regulation of the blood glucose level but its mechanism is yet to be confirmed.[28][29]
The receptor-binding domain (RBD) of spike protein, located on the virus’s surface, specifically attaches to human cell receptors.[38] ACE2 is essential as it’s a cell surface receptor that lets the virus get into and infect cells. The spike protein’s RBD of SARS-CoV-2 links to ACE2, enabling viral entry and reproduction within cells.[38] In addition the attachment of SP-A and SP-D residues to ACE2 could potentially diminish the strength of the interaction between the spike protein and ACE2.[38]
The binding of the SARS-CoV-2 virus through mACE2 receptors present in heart tissue may be responsible for direct viral injury leading to myocarditis. In a study done during the SARS outbreak, SARS virus RNA was ascertained in the autopsy of heart specimens in 35% of the patients who died due to SARS.[42] It was also observed that an already diseased heart has increased expression of mACE2 receptors contrasted to healthy individuals.[43] This entry process also requires priming of the S protein by the host serine proteaseTMPRSS2, the inhibition of which is under current investigation as a potential therapeutic.[44][21] It has also been shown that disruption of S-proteinglycosylation significantly impairs viral entry, indicating the importance ofglycan-protein interactions in the process.[45]
This has led some to hypothesize that decreasing the levels of mACE2, in cells, might help in fighting the infection. Furthermore, according to studies conducted onmice, the interaction of the spike protein of the coronavirus with mACE2 induces a drop in the levels of mACE2 in cells through internalization and degradation of the protein and hence may contribute to lung damage.[46][47]
On the other hand, sACE2 has been shown to have a protective effect against virus-induced lung injury by increasing the production of thevasodilatorangiotensin 1–7.[46] Furthermore, some researchers have hypothesized that sACE2 (which is created during the Protective Phase of RAAS) is not only involved in binding to angiotensin II to create angiotensin I-7, which lowers blood pressure by vasodilation, but that free and soluble ACE2 may also be binding tocoronavirus spike proteins, hence making those coronavirus spikes unavailable for binding to mACE-2 sites.[37] But even with only tiny amounts of mACE2, SARS-CoV-2 virus can gain entry into cells if TMPRSS2 is present.[48]
BothACE inhibitors andangiotensin II receptor blockers (ARBs) that are used to treat high blood pressure have been shown in rodent studies to upregulate mACE2 expression, possibly affecting the severity of coronavirus infections.[49][50]
However, asystematic review andmeta-analysis published on July 11, 2012, found that "use of ACE inhibitors was associated with a significant 34% reduction in risk of pneumonia compared with controls." Moreover, "the risk of pneumonia was also reduced in patients treated with ACE inhibitors who were at higher risk of pneumonia, in particular those with stroke and heart failure. Use of ACE inhibitors was also associated with a reduction in pneumonia related mortality, although the results were less robust than for overall risk of pneumonia."[51] An April 2020 study of patients hospitalized in Hubei Province in China found a death rate of 3.7% for patients with hypertension who were taking ACE inhibitors or ARBs. The death rate was compared with 9.8% of hospitalized patients with hypertension not taking such drugs, suggesting that ACE inhibitors and ARBs are not harmful and may help against the coronavirus.[52]
Despite lack of conclusive evidence, some have advocated for or against the cessation of ACE inhibitor or ARB treatment in COVID-19 patients with hypertension.[53] However, multiple professional societies and regulatory bodies have recommended continuing standard ACE inhibitor and ARB therapy.[54][55][56]
Plasma ACE2 levels predict outcome of COVID-19 in hospitalized patients, with higher plasma levels being correlated with worse disease outcomes. Patients with high blood pressure or heart disease show elevated ACE2 plasma levels.[57]
Given its role as the SARS-CoV-2 entry receptor, it has been repeatedly hypothesised that population variation in ACE2 may contribute to an individual'sgenetic susceptibility to COVID-19.[58][59] Several studies have reported that ACE2missense variants can alter itsbinding affinity for the spike protein,[60][61][62] and consequently its susceptibility to SARS-CoV-2 pseudovirus entry,[63] and there is strong evidence of individuals who carry rare variants in ACE2 that could confer total resistance to SARS-CoV-2 infection.[62] The expression level of ACE2 at the cell surface is another critical factor affecting viral susceptibility and probably plays a role in the tissue tropism of the virus[63] and many suspected COVID-19 associated ACE2 variants affect expression.[59] In fact, SARS-CoV-2's viral tropism is dependent on ACE2 tissue distribution and expression.[64] For example, genetic variants placed in the X chromosome (rs190509934:C) have been related to lower expression levels of ACE2 enzyme. This would lead to an increased number of entries and infections performed by the SARS-CoV-2 virus. Moreover, those variants have shown a 37% reduction in expression of the protein and a remarkable protection from severe outcomes (respiratory failure and death).[65]
Recombinant human ACE2 (rhACE2) is surmised to be a novel therapy foracute lung injury, and appeared to improve pulmonaryblood flow andoxygen saturation inpiglets with alipopolysaccharide-inducedacute respiratory distress syndrome.[66] The half-life of rhACE2 in human beings is about 10 hours, and the onset of action is 30 minutes in addition to the course of effect (duration) of 24 hours.[66] Several findings suggest that rhACE2 may be a promising drug for those with intolerance to classicrenin–angiotensin system inhibitors (RAS inhibitors) or in diseases where circulating angiotensin II is elevated.[66]
Anin vitro study focused on the early stages of infection found that clinical-grade human recombinant soluble ACE2 (hrsACE2) reduced SARS-CoV-2 recovery fromvero cells by a factor of 1,000–5,000. The equivalent mouse rsACE2 did not have such an effect. This study suggests that rhsACE2 not only restores the renin-angiotensin system to balance as in the earlier ARDS studies, but also directly slows down infection by this virus – possibly as a decoy.[67] ACE2 mutants have been engineered with even higher affinity for SARS-CoV-2 Spike and shown to effectively neutralise the virusin vitro.[68] An ACE2 triple mutant that displayed nanomolar binding to Spike (sACE2.v2.4),[68] was later shown to block pseudovirus cell entry in human lung cell lines and prevent SARS-CoV-2 induced ARDS in an ACE2 humanized mouse model.[69]
Infused rhACE2 has been evaluated in clinical trials for the treatment ofacute respiratory distress syndrome (ARDS).[70] rhACE2 is in phase II trial for severe COVID-19.[71]
^Chamsi-Pasha MA, Shao Z, Tang WH (March 2014)."Angiotensin-converting enzyme 2 as a therapeutic target for heart failure".Current Heart Failure Reports.11 (1). Springer Science and Business Media LLC:58–63.doi:10.1007/s11897-013-0178-0.PMC3944399.PMID24293035.The discovery of ACE2 and its role in counteracting the effect of Ang-II through Ang(1-7) formation ... An imbalance in ACE2/Ang-(1–7) and ACE/Ang-II axes is critical in the development of cardiovascular diseases. The central role of ACE2, therefore, appears to counter ACE activity by reducing Ang-II bioavailability and increasing Ang(1-7) formation ... The use of RAS-modulating agents and molecules as novel therapeutic agents in hypertension and cardiovascular therapeutic research.
^abcdTurner AJ (2015). "Chapter 25: ACE2 Cell Biology, Regulation, and Physiological Functions". In Unger T, Ulrike M, Steckelings UM, dos Santos RA (eds.).The Protective Arm of the Renin Angiotensin System (RAS): Functional Aspects and Therapeutic Implications. Academic Press. pp. 185–189.doi:10.1016/B978-0-12-801364-9.00025-0.ISBN978-0-12-801364-9.S2CID88645177.
^Niu MJ, Yang JK, Lin SS, Ji XJ, Guo LM (2008). "Loss of angiotensin-converting enzyme 2 leads to impaired glucose homeostasis in mice".Endocrine.34 (1–3):56–61.doi:10.1007/s12020-008-9110-x.PMID18956256.S2CID46331895.
^Fehr AR, Perlman S (2015). "Coronaviruses: an overview of their replication and pathogenesis".Coronaviruses. Methods in Molecular Biology. Vol. 1282. Springer New York. pp. 1–23.doi:10.1007/978-1-4939-2438-7_1.ISBN978-1-4939-2437-0.PMC4369385.PMID25720466.Many α-coronaviruses utilize aminopeptidase N (APN) as their receptor, SARS-CoV and HCoV-NL63 use angiotensin-converting enzyme 2 (ACE2) as their receptor, MHV enters through CEACAM1, and the recently identified MERS-CoV binds to dipeptidyl-peptidase 4 (DPP4) to gain entry into human cells (See Table 1 for a list of known CoV receptors).
^Jia H (September 2016). "Pulmonary Angiotensin-Converting Enzyme 2 (ACE2) and Inflammatory Lung Disease".Shock.46 (3):239–248.doi:10.1097/SHK.0000000000000633.PMID27082314.S2CID3639219.Once SARS-CoV binds to its receptor, the abundance on the cell surface, mRNA expression and the enzymatic activity of ACE2 are significantly reduced. ... These effects are, in part, due to enhanced shedding/internalizing processes. ... The spike protein binds to ACE2 and subsequently down regulated ACE2 protein expression and resulted in worsened acid aspiration pneumonia
^Santos TM, Lisboa AB, Rodrigues W, Gomes H, Abrahão J, Del-Bem LE (February 2022). "Human variation in the protein receptor ACE2 affects its binding affinity to SARS-CoV-2 in a variant-dependent manner".Journal of Biomolecular Structure & Dynamics.41 (7):2947–2955.doi:10.1080/07391102.2022.2042387.PMID35196964.S2CID247083671.
