Biology:Angiotensin-converting enzyme 2

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Short description: Exopeptidase enzyme that acts on angiotensin I and II


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


Angiotensin-converting enzyme 2 (ACE2)[1] is an enzyme that can be found either attached to the membrane of cells (mACE2) in the intestines, kidney, testis, gallbladder, and heart or in a soluble form (sACE2).[2][3][4] Both membrane bound and soluble ACE2 are integral parts of the renin–angiotensin–aldosterone system (RAAS) that exists to keep the body's blood pressure in check. mACE2 is cleaved by the enzyme ADAM17 that releases its extracellular domain, creating soluble ACE2 (sACE2).[5] ACE2 enzyme activity opposes the classical arm of the RAAS by lowering blood pressure through catalyzing the hydrolysis of angiotensin II (a vasoconstrictor peptide which raises blood pressure) into angiotensin (1–7) (a vasodilator).[4][6][7] Angiotensin (1-7) in turns binds to MasR receptors creating localized vasodilation and hence decreasing blood pressure.[8] This decrease in blood pressure makes the entire process a promising drug target for treating cardiovascular diseases.[9][10]

mACE2 also serves as the entry point into cells for some coronaviruses, including HCoV-NL63, SARS-CoV, and SARS-CoV-2.[1] The SARS-CoV-2 spike protein itself is known to damage the endothelium via downregulation of ACE2.[11] The human version of the enzyme can be referred to as hACE2.[12]

Structure

Angiotensin-converting enzyme 2
Identifiers
EC number3.4.17.23
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum

Membrane bound angiotensin-converting enzyme 2 (mACE2) is a zinc-containing metalloenzyme located on the surface of intestinal enterocytes, renal tubular cells and other cells.[2][13] mACE2 protein contains an N-terminal peptidase M2 domain and a C-terminal collectrin renal amino acid transporter domain.[13]

mACE2 is a single-pass type I membrane protein, with its enzymatically active domain exposed on the surface of cells in the intestines and other tissues.[2][3] The extracellular domain of mACE2 can be cleaved from the transmembrane domain by another enzyme known as ADAM17 a member of the sheddase enzyme family, during the protective phase of RAAS, the Renin–Angiotension–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.[14][15]

Location within the human body

mACE2 is attached to the cell membrane of mainly enterocytes of the small intestine and duodenum, proximal tubular cells of the kidneys, glandular cells of the gallbladder, as well as Sertoli cells and Leydig cells of the testis.[2] The expression profile of mACE2 in the human body was recently thoroughly evaluated by the Human Protein Atlas team using a large-scale multiomics approach combining several different methods for analysis of gene expression, including a stringent immunohistochemical analysis using two independent antibodies.[2][16] In addition to the above-mentioned issues, mACE2 expression was also seen in endothelial cells and pericytes of blood vessels within certain tissues, cardiomyocytes in heart tissue, and a smaller subset of cells within the thyroid gland, epididymis, seminal vesicle, pancreas, liver and placenta. Despite the fact that the respiratory system is the primary route of SARS-CoV-2 infection, very limited expression is seen, both at protein and mRNA level. The expression within the respiratory system is mainly restricted to the upper bronchial and nasal epithelia, especially in the ciliated cells.[17]

Function

As part of the renin–angiotensin–aldosterone system (RAAS) protective phase, soluble ACE2's (sACE2) important function is to act as a counterbalance to the angiotensin-converting enzyme (ACE). ACE cleaves angiotensin I hormone into the vasoconstricting angiotensin 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 into angiotensin (1-7), thereby lowering blood pressure.[18][19]

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 vasodilator angiotensin (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.[20][13] sACE2 can also cleave numerous peptides, including [des-Arg9]-bradykinin, apelin, neurotensin, dynorphin A, and ghrelin.[13]

mACE2 also regulates the membrane trafficking of the neutral amino acid transporter SLC6A19 and has been implicated in Hartnup's disease.[21][22][23]

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.[24][25]

Coronavirus entry point

As a transmembrane protein, mACE2 serves as the main entry point into cells for some coronaviruses, including HCoV-NL63,[1] SARS-CoV (the virus that causes SARS),[26][27][28] and SARS-CoV-2[29] (the virus that causes COVID-19).[30][31][32][33] More specifically, the binding of the spike S1 protein of SARS-CoV and SARS-CoV-2 to the enzymatic domain of mACE2 on the surface of cells results in endocytosis and translocation of both the virus and the enzyme into endosomes located within cells.[34][35] In culture blocking endocytosis traps the virus on the surface.[36]

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.[37] It was also observed that an already diseased heart has increased expression of mACE2 receptors contrasted to healthy individuals.[38] This entry process also requires priming of the S protein by the host serine protease TMPRSS2, the inhibition of which is under current investigation as a potential therapeutic.[39][17] It has also been shown that disruption of S-protein glycosylation significantly impairs viral entry, indicating the importance of glycan-protein interactions in the process.[40]

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 on mice, 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.[41][42]

On the other hand, sACE2 has been shown to have a protective effect against virus-induced lung injury by increasing the production of the vasodilator angiotensin 1–7.[41] 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 to coronavirus spike proteins, hence making those coronavirus spikes unavailable for binding to mACE-2 sites.[33] But even with only tiny amounts of mACE2, SARS-CoV-2 virus can gain entry into cells if TMPRSS2 is present.[43]

Both ACE inhibitors and angiotensin 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.[44][45]

However, a systematic review and meta-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."[46] 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.[47]

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.[48] However, multiple professional societies and regulatory bodies have recommended continuing standard ACE inhibitor and ARB therapy.[49][50][51]

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.[52]

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's genetic susceptibility to COVID-19.[53][54] Several studies have reported that ACE2 missense variants can alter its binding affinity for the spike protein,[55][56][57] and consequently its susceptibility to SARS-CoV-2 pseudovirus entry,[58] and there is strong evidence of individuals who carry rare variants in ACE2 that could confer total resistance to SARS-CoV-2 infection.[57] 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[58] and many suspected COVID-19 associated ACE2 variants affect expression.[54] In fact, SARS-CoV-2's viral tropism is dependent on ACE2 tissue distribution and expression.[59] 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).[60]

Recombinant human ACE2

Recombinant human ACE2 (rhACE2) is surmised to be a novel therapy for acute lung injury, and appeared to improve pulmonary blood flow and oxygen saturation in piglets with a lipopolysaccharide-induced acute respiratory distress syndrome.[61] 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.[61] Several findings suggest that rhACE2 may be a promising drug for those with intolerance to classic renin–angiotensin system inhibitors (RAS inhibitors) or in diseases where circulating angiotensin II is elevated.[61]

An in vitro study focused on the early stages of infection found that clinical-grade human recombinant soluble ACE2 (hrsACE2) reduced SARS-CoV-2 recovery from vero 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.[62] ACE2 mutants have been engineered with even higher affinity for SARS-CoV-2 Spike and shown to effectively neutralise the virus in vitro.[63] An ACE2 triple mutant that displayed nanomolar binding to Spike (sACE2.v2.4),[63] 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.[64]

Infused rhACE2 has been evaluated in clinical trials for the treatment of acute respiratory distress syndrome (ARDS).[65] rhACE2 is in phase II trial for severe COVID-19.[66]

See also

References

  1. ↑ 1.0 1.1 1.2 "Gene: ACE2, angiotensin I converting enzyme 2". National Center for Biotechnology Information (NCBI). U.S. National Library of Medicine. 2020-02-28. https://www.ncbi.nlm.nih.gov/gene/59272. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 "The protein expression profile of ACE2 in human tissues". Molecular Systems Biology 16 (7): e9610. July 2020. doi:10.15252/msb.20209610. PMID 32715618. 
  3. ↑ 3.0 3.1 "Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis". The Journal of Pathology 203 (2): 631–637. June 2004. doi:10.1002/path.1570. PMID 15141377. 
  4. ↑ 4.0 4.1 "A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9". Circulation Research 87 (5): E1–E9. September 2000. doi:10.1161/01.RES.87.5.e1. PMID 10969042. 
  5. ↑ Lambert, Daniel W.; Yarski, Mike; Warner, Fiona J.; Thornhill, Paul; Parkin, Edward T.; Smith, A. Ian; Hooper, Nigel M.; Turner, Anthony J. (August 2005). "Tumor Necrosis Factor-α Convertase (ADAM17) Mediates Regulated Ectodomain Shedding of the Severe-acute Respiratory Syndrome-Coronavirus (SARS-CoV) Receptor, Angiotensin-converting Enzyme-2 (ACE2)" (in en). Journal of Biological Chemistry 280 (34): 30113–30119. doi:10.1074/jbc.M505111200. PMID 15983030. PMC 8062222. https://linkinghub.elsevier.com/retrieve/pii/S0021925820794330. 
  6. ↑ "ACE2 of the heart: From angiotensin I to angiotensin (1-7)". Cardiovascular Research 73 (3): 463–469. February 2007. doi:10.1016/j.cardiores.2006.09.006. PMID 17049503. 
  7. ↑ "Angiotensin-Converting Enzyme 2 Metabolizes and Partially Inactivates Pyr-Apelin-13 and Apelin-17: Physiological Effects in the Cardiovascular System". Hypertension 68 (2): 365–377. August 2016. doi:10.1161/HYPERTENSIONAHA.115.06892. PMID 27217402. 
  8. ↑ "Angiotensin-converting enzyme 2 as a therapeutic target for heart failure". Current Heart Failure Reports (Springer Science and Business Media LLC) 11 (1): 58–63. March 2014. doi:10.1007/s11897-013-0178-0. PMID 24293035. "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.". 
  9. ↑ "Angiotensin-converting enzyme 2 as a therapeutic target for heart failure". Current Heart Failure Reports (Springer Science and Business Media LLC) 11 (1): 58–63. March 2014. doi:10.1007/s11897-013-0178-0. PMID 24293035. "Studies with recombinant human ACE2 (rhACE2) have shown beneficial cardiac effects [18, 36]. rhACE2 has anti-fibrotic properties and can attenuate effect on systolic and diastolic dysfunction, presumably via Ang-II inhibition.". 
  10. ↑ "Angiotensin II and angiotensin 1-7: which is their role in atrial fibrillation?". Heart Failure Reviews (Springer Science and Business Media LLC) 25 (2): 367–380. March 2020. doi:10.1007/s10741-019-09837-7. PMID 31375968. http://openaccess.sgul.ac.uk/111404/1/Manuscript%20Ang-AF.docx. "the possibility of using the A1-7 or ACE2 analogues, to enlarge current therapeutic options for AF, may represent an important field of research.". 
  11. ↑ "SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2". Circulation Research 128 (9): 1323–1326. April 2021. doi:10.1161/CIRCRESAHA.121.318902. PMID 33784827. 
  12. ↑ "Coronaviridae: 100,000 Years of Emergence and Reemergence". Emerging and Reemerging Viral Pathogens: Fundamental and Basic Virology Aspects of Human, Animal and Plant Pathogens. 1. Elsevier. 2019. p. 135. ISBN 978-0-12-819400-3. https://books.google.com/books?id=4l6wDwAAQBAJ&pg=PA135. 
  13. ↑ 13.0 13.1 13.2 13.3 "Chapter 25: ACE2 Cell Biology, Regulation, and Physiological Functions". The Protective Arm of the Renin Angiotensin System (RAS): Functional Aspects and Therapeutic Implications. Academic Press. 2015. pp. 185–189. doi:10.1016/B978-0-12-801364-9.00025-0. ISBN 978-0-12-801364-9. 
  14. ↑ "Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2)". The Journal of Biological Chemistry 280 (34): 30113–30119. August 2005. doi:10.1074/jbc.M505111200. PMID 15983030. 
  15. ↑ "Angiotensin II induced proteolytic cleavage of myocardial ACE2 is mediated by TACE/ADAM-17: a positive feedback mechanism in the RAS". Journal of Molecular and Cellular Cardiology 66: 167–176. January 2014. doi:10.1016/j.yjmcc.2013.11.017. PMID 24332999. 
  16. ↑ The Human Protein Atlas. "ACE2 protein expression summary". https://www.proteinatlas.org/ENSG00000130234-ACE2. 
  17. ↑ 17.0 17.1 "Mechanisms of SARS-CoV-2 entry into cells". Nature Reviews. Molecular Cell Biology 23 (1): 3–20. January 2022. doi:10.1038/s41580-021-00418-x. PMID 34611326. 
  18. ↑ "Regulation of Angiotensin-Converting Enzyme 2: A Potential Target to Prevent COVID-19?". Frontiers in Endocrinology 12: 725967. 2021. doi:10.3389/fendo.2021.725967. PMID 34745001. 
  19. ↑ "Angiotensin-converting enzyme 2 as a potential therapeutic target for COVID-19: A review". Journal of Pharmaceutical Analysis 12 (2): 215–220. December 2021. doi:10.1016/j.jpha.2021.12.003. PMID 34934510. 
  20. ↑ "Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas". Proceedings of the National Academy of Sciences of the United States of America 100 (14): 8258–8263. July 2003. doi:10.1073/pnas.1432869100. PMID 12829792. Bibcode: 2003PNAS..100.8258S. 
  21. ↑ "A protein complex in the brush-border membrane explains a Hartnup disorder allele". FASEB Journal 22 (8): 2880–2887. August 2008. doi:10.1096/fj.08-107300. PMID 18424768. 
  22. ↑ "Molecular basis for the interaction of the mammalian amino acid transporters B0AT1 and B0AT3 with their ancillary protein collectrin". The Journal of Biological Chemistry 290 (40): 24308–24325. October 2015. doi:10.1074/jbc.M115.648519. PMID 26240152. 
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  25. ↑ "The renin-angiotensin system: a target of and contributor to dyslipidemias, altered glucose homeostasis, and hypertension of the metabolic syndrome". American Journal of Physiology. Heart and Circulatory Physiology 302 (6): H1219–H1230. March 2012. doi:10.1152/ajpheart.00796.2011. PMID 22227126. 
  26. ↑ "Coronaviruses: an overview of their replication and pathogenesis". Coronaviruses. Methods in Molecular Biology. 1282. Springer New York. 2015. pp. 1–23. doi:10.1007/978-1-4939-2438-7_1. ISBN 978-1-4939-2437-0. "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)." 
  27. ↑ "Receptor recognition and cross-species infections of SARS coronavirus". Antiviral Research 100 (1): 246–254. October 2013. doi:10.1016/j.antiviral.2013.08.014. PMID 23994189. 
  28. ↑ "A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury". Nature Medicine 11 (8): 875–879. August 2005. doi:10.1038/nm1267. PMID 16007097. 
  29. ↑ "What are the official names of the disease and the virus that causes it?". World Health Organization. https://www.who.int/news-room/q-a-detail/q-a-coronaviruses. 
  30. ↑ "A pneumonia outbreak associated with a new coronavirus of probable bat origin". Nature 579 (7798): 270–273. March 2020. doi:10.1038/s41586-020-2012-7. PMID 32015507. Bibcode: 2020Natur.579..270Z. 
  31. ↑ "Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission". Science China Life Sciences 63 (3): 457–460. March 2020. doi:10.1007/s11427-020-1637-5. PMID 32009228. 
  32. ↑ "COVID-19 Vaccine Will Close in on the Spikes". Public Library of Science. 2020-02-20. https://blogs.plos.org/dnascience/2020/02/20/covid-19-vaccine-will-close-in-on-the-spikes/. 
  33. ↑ 33.0 33.1 "ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19". Frontiers in Immunology 11: 576745. 2020. doi:10.3389/fimmu.2020.576745. PMID 33117379. 
  34. ↑ "SARS coronavirus entry into host cells through a novel clathrin- and caveolae-independent endocytic pathway". Cell Research 18 (2): 290–301. February 2008. doi:10.1038/cr.2008.15. PMID 18227861. 
  35. ↑ "Physiological and molecular triggers for SARS-CoV membrane fusion and entry into host cells". Virology 517: 3–8. April 2018. doi:10.1016/j.virol.2017.12.015. PMID 29275820. 
  36. ↑ "Getting in on the action: New tools to see SARS-CoV-2 infect a cell". Cell Chemical Biology 30 (3): 233–234. March 2023. doi:10.1016/j.chembiol.2023.02.010. PMID 36931249. 
  37. ↑ "SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS". European Journal of Clinical Investigation 39 (7): 618–625. July 2009. doi:10.1111/j.1365-2362.2009.02153.x. PMID 19453650. 
  38. ↑ "Myocarditis associated with Covid-19 disease: A systematic review of published case reports and case series". International Journal of Clinical Practice 75 (11): e14470. November 2021. doi:10.1111/ijcp.14470. PMID 34235815. 
  39. ↑ "COVID-19 and the Heart". Circulation Research 126 (10): 1443–1455. May 2020. doi:10.1161/CIRCRESAHA.120.317055. PMID 32252591. 
  40. ↑ "Understanding Glycans in COVID-19 Drug Design" (in en-US). Genetic Engineering and Biotechnology News. 1 April 2020. https://www.genengnews.com/insights/understanding-glycans-in-covid-19-drug-design/. 
  41. ↑ 41.0 41.1 "The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice". Experimental Physiology 93 (5): 543–548. May 2008. doi:10.1113/expphysiol.2007.040048. PMID 18448662. 
  42. ↑ "Pulmonary Angiotensin-Converting Enzyme 2 (ACE2) and Inflammatory Lung Disease". Shock 46 (3): 239–248. September 2016. doi:10.1097/SHK.0000000000000633. PMID 27082314. "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". 
  43. ↑ "Mechanisms of SARS-CoV-2 Transmission and Pathogenesis". Trends in Immunology 41 (12): 1100–1115. December 2020. doi:10.1016/j.it.2020.10.004. PMID 33132005. 
  44. ↑ "Good ACE, bad ACE do battle in lung injury, SARS". Nature Medicine 11 (8): 821–822. August 2005. doi:10.1038/nm0805-821. PMID 16079870. 
  45. ↑ "Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19". Journal of Travel Medicine 27 (3). May 2020. doi:10.1093/jtm/taaa041. PMID 32186711. 
  46. ↑ "Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: systematic review and meta-analysis". BMJ 345 (jul11 1): e4260. July 2012. doi:10.1136/bmj.e4260. PMID 22786934. "Our results suggest an important role of ACE inhibitors, but not ARBs, in reducing the risk of pneumonia. These data may discourage the withdrawal of ACE inhibitors in some patients with tolerable adverse events (namely, cough) who are at particularly high risk of pneumonia. ACE inhibitors also lowered the risk of pneumonia related mortality, mainly in patients with established disease, but the robustness of the evidence was weaker.". 
  47. ↑ "Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19". Circulation Research 126 (12): 1671–1681. June 2020. doi:10.1161/CIRCRESAHA.120.317134. PMID 32302265. 
  48. ↑ "COVID-19 and Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: What Is the Evidence?". JAMA 323 (18): 1769–1770. May 2020. doi:10.1001/jama.2020.4812. PMID 32208485. 
  49. ↑ "Position Statement of the ESC Council on Hypertension on ACE-Inhibitors and Angiotensin Receptor Blockers". European Society of Cardiology (ESC). 13 March 2020. https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang. 
  50. ↑ "EMA advises continued use of medicines for hypertension, heart or kidney disease during COVID-19 pandemic". European Medicines Agency (EMA). 27 March 2020. https://www.ema.europa.eu/en/news/ema-advises-continued-use-medicines-hypertension-heart-kidney-disease-during-covid-19-pandemic. 
  51. ↑ "HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19". American College of Cardiology (ACC). 27 March 2020. https://www.acc.org/latest-in-cardiology/articles/2020/03/17/08/59/hfsa-acc-aha-statement-addresses-concerns-re-using-raas-antagonists-in-covid-19. 
  52. ↑ "Plasma ACE2 predicts outcome of COVID-19 in hospitalized patients". PLOS ONE 16 (6): e0252799. 2021. doi:10.1371/journal.pone.0252799. PMID 34086837. Bibcode: 2021PLoSO..1652799K. 
  53. ↑ "Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations". Cell Discovery 6 (1): 11. 2020-02-24. doi:10.1038/s41421-020-0147-1. PMID 32133153. 
  54. ↑ 54.0 54.1 "Polymorphisms and mutations of ACE2 and TMPRSS2 genes are associated with COVID-19: a systematic review". European Journal of Medical Research 27 (1): 26. February 2022. doi:10.1186/s40001-022-00647-6. PMID 35193695. 
  55. ↑ "Human ACE2 receptor polymorphisms and altered susceptibility to SARS-CoV-2". Communications Biology 4 (1): 475. April 2021. doi:10.1038/s42003-021-02030-3. PMID 33846513. 
  56. ↑ "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. February 2022. doi:10.1080/07391102.2022.2042387. PMID 35196964. 
  57. ↑ 57.0 57.1 "Missense variants in human ACE2 strongly affect binding to SARS-CoV-2 Spike providing a mechanism for ACE2 mediated genetic risk in Covid-19: A case study in affinity predictions of interface variants". PLOS Computational Biology 18 (3): e1009922. March 2022. doi:10.1371/journal.pcbi.1009922. PMID 35235558. Bibcode: 2022PLSCB..18E9922M. 
  58. ↑ 58.0 58.1 "Mutants of human ACE2 differentially promote SARS-CoV and SARS-CoV-2 spike mediated infection". PLOS Pathogens 17 (7): e1009715. July 2021. doi:10.1371/journal.ppat.1009715. PMID 34270613. 
  59. ↑ "Angiotensin-converting enzyme 2-at the heart of the COVID-19 pandemic". Cell 186 (5): 906–922. March 2023. doi:10.1016/j.cell.2023.01.039. PMID 36787743. 
  60. ↑ "The human genetic epidemiology of COVID-19". Nature Reviews. Genetics 23 (9): 533–546. September 2022. doi:10.1038/s41576-022-00478-5. PMID 35501396. 
  61. ↑ 61.0 61.1 61.2 "Interference With the Renin–Angiotensin System (RAS): Classical Inhibitors and Novel Approaches". Encyclopedia of Endocrine Diseases. Elsevier. 2019. pp. 523–530. doi:10.1016/b978-0-12-801238-3.65341-2. ISBN 978-0-12-812200-6. 
  62. ↑ "Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2". Cell 181 (4): 905–913.e7. May 2020. doi:10.1016/j.cell.2020.04.004. PMID 32333836. 
  63. ↑ 63.0 63.1 "Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2". Science 369 (6508): 1261–1265. September 2020. doi:10.1126/science.abc0870. PMID 32753553. Bibcode: 2020Sci...369.1261C. 
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  66. ↑ "Apeiron Biologics moves forward with APN01 for treatment of COVID-19". www.thepharmaletter.com. https://www.thepharmaletter.com/article/apeiron-biologics-moves-forward-with-apn01-for-treatment-of-covid-19. 

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