Evaluation of Angiotensin-converting Enzyme 2 (ACE2) in COVID-19: A Systematic Review on All Types of Studies for Epidemiologic, Diagnostic, and Therapeutic Purposes

Angiotensin-converting enzyme 2 (ACE2) in COVID-19


  • Houshang Nemati Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
  • Mazaher Ramezani
  • Farid Najafi Research Center for Environmental Determinants of Health, School of Public Health, Kermanshah, Iran
  • Babak Sayad Department of Infectious Disease, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
  • Mehri Nazeri Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
  • Masoud Sadeghi Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran




Angiotensin-converting enzyme 2, novel coronavirus 2019, COVID-19, systematic review


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the angiotensin-converting enzyme 2 (ACE2) receptor of SARS-CoV for cell entry. We aimed to check the association between ACE2 and COVID-19 (coronavirus disease 2019) in a systematic review. Two databases (PubMed/Medline and Scopus) and bioRxiv were checked for retrieving all types of studies in relation to ACE2 and COVID-19 until March 18, 2020. Forty-one studies were entered to the systematic review. These studies included nineteen original, eight reviews, four letters to the editor, three research papers, one correspondence, one commentary, one mini review, two reports, one opinion, and one perspective. In summary, the results showed that the ACE2 receptor for COVID-19 is similar to that of SARS-CoV. However, its expression was different in various populations as well as in the two genders. ACE2 may be used as a therapeutic target. Patients who take ACE inhibitors may have benefit in severe disease outcomes. Finally, pangolins and snakes and turtles may act as the potential intermediate hosts transmitting disease to humans.


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World Health Organization. Coronavirus Disease (COVID-19) Outbreak. Available from: https://www.who.int/emergencies/ diseases/novel-coronavirus-2019. [Last accessed on 2020 Mar 05].

Cheng ZJ, Shan J. 2019 novel coronavirus: Where we are and what we know. Infection. 2020;48(2):155-63. https://doi. org/10.1007/s15010-020-01401-y PMid:32072569

Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. Discovery of a novel coronavirus associated with the recent pneumonia outbreak in humans and its potential bat origin. BioRxiv. 2020;2020:914952. https://doi. org/10.1101/2020.01.22.914952

Diaz JH. Hypothesis: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19. J Travel Med. 2020;27(3):taaa041. https:// doi.org/10.1093/jtm/taaa041 PMid:32186711

Crackower MA, Sarao R, Oudit GY, Yagil C, Kozieradzki I, Scanga SE, et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature. 2002;417(6891):822-8. https://doi.org/10.1038/nature00786 PMid:12075344

Hulswit R, de Haan C, Bosch BJ. Coronavirus spike protein and tropism changes. Adv Virus Res. 2016;96:29-57. https://doi. org/10.1016/bs.aivir.2016.08.004 PMid:27712627

Li F. Structure, function, and evolution of coronavirus spike proteins. Annu Rev Virol. 2016;3(1):237-61. https://doi. org/10.1146/annurev-virology-110615-042301 PMid:27578435

Belouzard S, Millet JK, Licitra BN, Whittaker GR. Mechanisms of coronavirus cell entry mediated by the viral spike protein. Viruses. 2012;4(6):1011-33. https://doi.org/10.3390/v4061011 PMid:22816037

Gallagher TM, Buchmeier MJ. Coronavirus spike proteins in viral entry and pathogenesis. Virology. 2001;279(2):371-4. https://doi.org/10.1006/viro.2000.0757 PMid:11162792

Li F, Li W, Farzan M, Harrison SC. Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science. 2005;309(5742):1864-8. https://doi.org/10.1126/ science.1116480 PMid:16166518

Meng T, Cao H, Zhang H, Kang Z, Xu D, Gong H, et al. The insert sequence in SARS-CoV-2 enhances spike protein cleavage by TMPRSS. BioRxiv. 2020;2020:926006. https://doi. org/10.1101/2020.02.08.926006

Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet. 2020;395(10224):565-74. PMid:32007145

Udugama B, Kadhiresan P, Kozlowski HN, Malekjahani A, Osborne M, Li V, et al. Diagnosing COVID-19: The disease and tools for detection. ACS Nano. 2020;14(4):0c02624. https://doi. org/10.1021/acsnano.0c02624 PMid:32223179

Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the COVID- 19 virus targeting the CNS: Tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem Neurosci. 2020;11(7):995-8. https://doi.org/10.1021/ acschemneuro.0c00122 PMid:32167747

Bao L, Deng W, Huang B, Gao H, Liu J, Ren L, et al. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice. BioRxiv. 2020;2020:939389. https://doi.org/10.1101/2020.02.07.939389

Batlle D, Wysocki J, Satchell K. Soluble angiotensin-converting enzyme 2: A potential approach for coronavirus infection therapy? Clin Sci (Lond). 2020;134(5):543-5. https://doi. org/10.1042/cs20200163 PMid:32167153

Brielle ES, Schneidman D, Linial M. The SARS-CoV-2 exerts a distinctive strategy for interacting with the ACE2 human receptor. BioRxiv. 2020;2020:986398. https://doi. org/10.1101/2020.03.10.986398

Cao Y, Li L, Feng Z, Wan S, Huang P, Sun X, et al. Comparative genetic analysis of the novel coronavirus (2019-nCoV/

SARS-CoV-2) receptor ACE2 in different populations. Cell Discov. 2020;6:11. https://doi.org/10.1038/s41421-020-0147-1 PMid:32133153

Chen J. Pathogenicity and transmissibility of 2019-nCoV-A quick overview and comparison with other emerging viruses. Microbes Infect. 2020;22(2):69-71. https://doi.org/10.1016/j. micinf.2020.01.004 PMid:32032682

Chen Y, Guo Y, Pan Y, Zhao ZJ. Structure analysis of the receptor binding of 2019-nCoV. Biochem Biophys Res Commun. 2020;525(1):135-40 PMid:32081428

Deng YY, Zheng Y, Cai GY, Chen XM, Hong Q. Single-cell RNA sequencing data suggest a role for angiotensin-converting enzyme 2 in kidney impairment in patients infected with 2019- nCoV. Chin Med J (Engl). 2020;133(9):1129-31. https://doi. org/10.1097/cm9.0000000000000783 PMid:32118645

Guan GW, Gao L, Wang JW, Wen XJ, Mao TH, Peng SW, et al. Exploring the mechanism of liver enzyme abnormalities in patients with novel coronavirus-infected pneumonia. Zhonghua Gan Zang Bing Za Zhi. 2020;28(2):E002. PMid:32077659

Guo YR, Cao QD, Hong ZS, Tan YY, Chen SD, Jin HJ, et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak-an update on the status. Mil Med Res. 2020;7(1):11. https://doi.org/10.1186/s40779-020-00240-0 PMid:32169119

Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res. 2020;2020:21656. https:// doi.org/10.1002/ddr.21656 PMid:32129518

Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271-80.e8. https://doi.org/10.1016/j. cell.2020.02.052 PMid:32142651

Kannan S, Ali PS, Sheeza A, Hemalatha K. COVID-19 (novel coronavirus 2019)-recent trends. Eur Rev Med Pharmacol Sci. 2020;24(4):2006-11. PMid:32141569

Kruse RL. Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China. F1000Res. 2020;9:72. https://doi.org/10.12688/f1000research.22211.2 PMid:32117569

Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol. 2020;5(4):562-9. https://doi. org/10.1038/s41564-020-0688-y PMid:32094589

Li JY, You Z, Wang Q, Zhou ZJ, Qiu Y, Luo R, et al. The epidemic of 2019-novel-coronavirus (2019-nCoV) pneumonia and insights for emerging infectious diseases in the future. Microbes Infect. 2020;22(2):80-5. https://doi.org/10.1016/j. micinf.2020.02.002 PMid:32087334

Li R, Qiao S, Zhang G. Analysis of angiotensin-converting enzyme 2 (ACE2) from different species sheds some light on cross-species receptor usage of a novel coronavirus 2019- nCoV. J Infect. 2020;80(4):469-6. https://doi.org/10.1016/j. jinf.2020.02.013 PMid:32092392

Liu Y, Yang Y, Zhang C, Huang F, Wang F, Yuan J, et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci. 2020;63(3):364-74. https://doi.org/10.1007/s11427-020-1643-8 PMid:32048163

Liu Z, Xiao X, Wei X, Li J, Yang J, Tan H, et al. Composition and divergence of coronavirus spike proteins and host ACE2 receptors predict potential intermediate hosts of SARS-CoV-2. J Med Virol. 2020;2020:25726. https://doi.org/10.1002/ jmv.25726 PMid:32100877

Lukassen S, Chua RL, Trefzer T, Kahn NC, Schneider MA, Muley T, et al. SARS-CoV-2 receptor ACE2 and TMPRSS2 are predominantly expressed in a transient secretory cell type in subsegmental bronchial branches. BioRxiv. 2020;2020:991455. https://doi.org/10.1101/2020.03.13.991455

Morse JS, Lalonde T, Xu S, Liu WR. Learning from the past: Possible urgent prevention and treatment options for severe acute respiratory infections caused by 2019-nCoV. Chembiochem. 2020;21(5):730-8. https://doi.org/10.1002/ cbic.202000047 PMid:32022370

Othman H, Bouslama Z, Brandenburg JT, Da Rocha J, Hamdi Y, Ghedira K, et al. In silico study of the spike protein from SARS-CoV-2 interaction with ACE2: Similarity with SARS-CoV, hot-spot analysis and effect of the receptor polymorphism. BioRxiv. 2020;2020:028. https://doi.org/10.1016/j.bbrc.2020.05.028

Su Z, Wu Y. A multiscale and comparative model for receptor binding of 2019 novel coronavirus and the implication of its life cycle in host cells. BioRxiv. 2020;2020:958272. https://doi. org/10.1101/2020.02.20.958272

Sun ML, Yang JM, Sun YP, Su GH. Inhibitors of RAS might be a good choice for the therapy of COVID-19 pneumonia. Zhonghua Jie He He Hu Xi Za Zhi. 2020;43(3):E014. PMid:32061198

Sun Z, Thilakavathy K, Kumar SS, He G, Liu SV. Potential factors influencing repeated SARS outbreaks in China. Int J Environ Res Public Health. 2020;17(5):E1633. https://doi. org/10.3390/ijerph17051633 PMid:32138266

Tian X, Li C, Huang A, Xia S, Lu S, Shi Z, et al. Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody. Emerg Microbes Infect. 2020;9(1):382-5. https://doi.org/10.1101/2020.01.28.923011 PMid:32065055

Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell. 2020;181(2):281-92.e6. https://doi. org/10.1016/j.cell.2020.02.058 PMid:32155444

Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020;367(6483):1260-3. https://doi.org/10.1126/science.abb2507 PMid:32075877

Wu Y. Compensation of ACE2 function for possible clinical management of 2019-nCoV-induced acute lung injury. Virol Sin. 2020;1:1-3. https://doi.org/10.1007/s12250-020-00205-6 PMid:32034638

Wu Y. Strong evolutionary convergence of receptor-binding protein spike between COVID-19 and SARS-related coronaviruses. BioRxiv. 2020;2020:975995. https://doi. org/10.1101/2020.03.04.975995

Xie L, Sun C, Luo C, Zhang Y, Zhang J, Yang J, et al. SARS-CoV-2 and SARS-CoV spike-RBD structure and receptor binding comparison and potential implications on neutralizing antibody and vaccine development. BioRxiv. 2020;2020:951723. https://doi.org/10.1101/2020.02.16.951723

Xu H, Zhong L, Deng J, Peng J, Dan H, Zeng X, et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci. 2020;12(1):8. https://doi. org/10.1038/s41368-020-0074-x PMid:32094336

Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. Science. 2020;367(6485):1444-8. https://doi.org/10.1126/ science.abb2762 PMid:32132184

Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: Molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020;46(4):586-90. https://doi.org/10.1007/ s00134-020-05985-9 PMid:32125455

Zhang Z, Wu Q, Zhang T. Pangolin homology associated with 2019-nCoV. BioRxiv. 2020;2020:950253. https://doi. org/10.1101/2020.02.19.950253

Zhao Y, Zhao Z, Wang Y, Zhou Y, Ma Y, Zuo W. Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCov. BioRxiv. 2020;2020:919985. https://doi. org/10.1101/2020.01.26.919985

Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270-3. PMid:32015507

Zou X, Chen K, Zou J, Han P, Hao J, Han Z. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019- nCoV infection. Front Med. 2020;14(2):185-92. https://doi. org/10.1007/s11684-020-0754-0 PMid:32170560

Chu KH, Tsang WK, Tang CS, Lam MF, Lai FM, To KF, et al. Acute renal impairment in coronavirus-associated severe acute respiratory syndrome. Kidney Int. 2005;67(2):698-705. https:// doi.org/10.1111/j.1523-1755.2005.67130.x PMid:15673319




How to Cite

Nemati H, Ramezani M, Najafi F, Sayad B, Nazeri M, Sadeghi M. Evaluation of Angiotensin-converting Enzyme 2 (ACE2) in COVID-19: A Systematic Review on All Types of Studies for Epidemiologic, Diagnostic, and Therapeutic Purposes: Angiotensin-converting enzyme 2 (ACE2) in COVID-19. Open Access Maced J Med Sci [Internet]. 2020 May 20 [cited 2022 Aug. 14];8(T1):84-91. Available from: https://oamjms.eu/index.php/mjms/article/view/4763

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