Роль мембранной и циркулирующей форм ACE 2 в развитии различных патологических процессов на фоне COVID-19

В обзоре литературы сделана попытка проанализировать ключевую информацию о функциях и патогенетическом значении ангиотензинпревращающего фермента 2 (ACE 2) у человека. ACE 2 участвует в развитии таких заболеваний, как артериальная гипертензия, мальабсорбция некоторых аминокислот в кишечнике, а также пневмония нового типа COVID-19, вызванная вирусом SARS-CoV-2. На основании современных источников дана оценка роли дифференциальной экспрессии рецепторных и растворимых форм этого белка в функционировании ренин-ангиотензин-альдостероновой системы, а также механизмов участия ACE2 в последовательном химическом превращении ангиотензина II и его влияния на функцию сердечно-сосудистой системы. Также затронута роль ACE2 в развитии воспалительных процессов в кишечнике и влиянии на состав кишечной микробиоты. Кроме того, в обзоре представлены обобщенные данные о протеолитической активации S-гликопротеина вируса SARS-CoV-2 и его участии вместе с ACE2 в процессе внедрения вируса в клетку-мишень. В заключение рассмотрена гипотеза аутоиммунных осложнений при COVID-19, связанных с образованием иммунного комплекса S-гликопротеин-ACE2 и выработкой аутоантител против него.

1. Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N. et al. A novel angiotensin‐converting enzyme‐related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Circ Res. 2000;87(5):E1-9. doi: 10.1161/01.res.87.5.e1.

2. Tipnis S, Hooper N, Hyde R, Karran E, Christie G, Turner A. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem. 2000;275(43):33238-43. doi: 10.1074/jbc.M002615200.

3. Hamming I, Timens W, Bulthuis M, Lely A, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203(2):631-7. doi: 10.1002/path.1570.

4. Doobay M, Talman L, Obr T, Tian X, Davisson R, Lazartigues E. Differential expression of neuronal ACE2 in transgenic mice with overexpression of the brain renin-angiotensin system. Am J Physiol Regul Integr Comp Physiol. 2007;292(1):R373-381. doi: 10.1152/ajpregu.00292.2006.

5. Harmer D, Gilbert M, Borman R, Clark K. Quantitative mRNA expression profiling of ACE 2, a novel homologue of angiotensin converting enzyme. FEBS Lett. 2002;532(1-2):107-110. doi: 10.1016/s0014-5793(02)03640-2.

6. Chen L, Li X, Chen M, Feng Y, Xiong C. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovasc Res. 2020;116:1097-1100. doi: 10.1093/cvr/cvaa078.

7. Lambert D, Yarski M, Warner F, Thornhill P, Parkin E, Smith A et al. 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). J Biol Chem. 2005;280:30113-30119. doi: 10.1074/jbc.M505111200.

8. Arendse L, Danser A, Poglitsch M, Touyz R, Burnett J, Llorens-Cortes C et al. Novel therapeutic approaches targeting the renin-angiotensin system and associated peptides in hypertension and heart failure. Pharmacol Rev. 2019;71:539-570. doi: 10.1124/pr.118.017129.

9. Shaltout H, Westwood B, Averill D, Ferrario C, Figueroa J, Diz D et al. Angiotensin metabolism in renal proximal tubules, urine, and serum of sheep: evidence for ACE2-dependent processing of angiotensin II. Am J Physiol Renal Physiol. 2007;292(1):F82-91. doi: 10.1152/ajprenal.00139.2006.

10. Úri K, Fagyas M, Siket I, Kertész A, Csanádi Z, Sándorfi G et al. New perspectives in the renin-angiotensin-aldosterone system (RAAS) IV: circulating ACE2 as a biomarker of systolic dysfunction in human hypertension and heart failure. PloS One, 2014;9(4), e87845. doi: 10.1371/journal.pone.0087845.

11. Epelman S, Tang WH, Chen SY, Van Lente F, Francis GS, Sen S. Detection of soluble angiotensin-converting enzyme 2 in heart failure: insights into the endogenous counter-regulatory pathway of the renin-angiotensin-aldosterone system. J Am Coll Cardiol. 2008;52(9):750-4. doi: 10.1016/j.jacc.2008.02.088.

12. Hashimoto T, Perlot T, Rehman A, Trichereau J, Ishiguro H, Paolino M et al. ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature. 2012;487:477-481. doi: 10.1038/nature11228.

13. 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):562-569. doi: 10.1038/s41564-020-0688-y.

14. Walls A, Park Y, Tortorici M, Wall A, McGuire A, Veesler D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein [published correction appears in Cell. 2020;183(6):1735]. Cell. 2020;181(2):281-292.e6. doi: 10.1016/j.cell.2020.02.058.

15. Zhang H, Penninger J, Li Y, Zhong N, Slutsky A. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020;46(4):586-590. doi: 10.1007/s00134-020-05985-9.

16. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506. doi: 10.1016/S0140-6736(20)30183-5.

17. World Health Organization. Hypertension and COVID-19 [Internet]. 17 June 2021, COVID-19: Scientific briefs. Available from: https://www.who.int/publications/i/item/WHO-2019-nCoV-Sci_Brief-Hypertension-2021.1 .

18. Surma S, Romańczyk M, Łabuzek K. Coronavirus SARS-Cov-2 and arterial hypertension - facts and myths. Pol Merkur Lekarski. 2020;48(285):195-198. PMID: 32564046.

19. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B. et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury. Nat Med. 2005;11:875–879. doi: 10.1038/nm1267.

20. Wang J, He W, Guo L, Zhang Y, Li H, Han S et al. The ACE2-Ang (1-7)-Mas receptor axis attenuates cardiac remodeling and fibrosis in post-myocardial infarction. Mol Med Rep. 2017;16(2):1973-1981. doi: 10.3892/mmr.2017.6848.

21. Zhu H, Zhang L, Ma Y, Zhai M, Xia L, Liu J et al. The role of SARS‐CoV‐2 target ACE2 in cardiovascular diseases. J Cell Mol Med. 2021;25(3):1342-1349. Published online 2021 Jan 14. doi: 10.1111/jcmm.16239.

22. Li XC, Zhang J, Zhuo JL. The vasoprotective axes of the renin-angiotensin system: Physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases. Pharmacol Res. 2017;125(Pt A):21-38. doi: 10.1016/j.phrs.2017.06.005.

23. Chaudhry F, Lavandero S, Xie X, Sabharwal B, Zheng YY, Correa A et al. Manipulation of ACE2 expression in COVID-19. Open Heart. 2020;7(2):e001424. doi: 10.1136/openhrt-2020-001424.

24. Шатунова П.О., Быков А.С., Свитич О.А., Зверев В.В. Ангиотензинпревращающий фермент 2. Подходы к патогенетической терапии covid-19. Журнал микробиологии, эпидемиологии и иммунобиологии. 2020;4:339-345

25. Danser A, Epstein M, Batlle D. Renin-Angiotensin System Blockers and the COVID-19 Pandemic: At Present There Is No Evidence to Abandon Renin-Angiotensin System Blockers. Hypertension. 2020;75(6):1382-1385. doi: 10.1161/HYPERTENSIONAHA.120.15082.

26. Nicin L, Abplanalp WT, Mellentin H, Kattih B, Tombor L, John D et al. Cell type-specific expression of the putative SARS-CoV-2 receptor ACE2 in human hearts. Eur Heart J. 2020;41(19):1804-1806. doi: 10.1093/eurheartj/ehaa311.

27. Фисун А.Я., Черкашин Д.В., Тыренко В.В., Жданов К.В., Козлов К.В. Роль ренин-ангиотензин-альдостероновой системы во взаимодействии с коронавирусом SARS-CoV-2 и в развитии стратегий профилактики и лечения новой коронавирусной инфекции (COVID-19). Артериальная гипертензия. 2020;26(3):248–262. doi:10.18705/1607-419X-2020-26-3-248-262.

28. Загидуллин Н.Ш., Гареева Д.Ф., Ишметов В.Ш., Павлов А.В., Плотникова М.Р., Пушкарева А.Э., Павлов В.Н. Ренин-ангиотензиновая система при новой коронавирусной инфекции COVID-2019. Артериальная гипертензия. 2020;26(3):240-247. https://doi.org/10.18705/1607-419X-2020-26-3-240-247.

29. Chu C, Zeng S, Hasan A, Hocher C, Krämer B, Hocher B. Comparison of infection risks and clinical outcomes in patients with and without SARS-CoV-2 lung infection under renin-angiotensin-aldosterone system blockade: Systematic review and meta-analysis. Br J Clin Pharmacol. 2021;87(6):2475-2492. doi: 10.1111/bcp.14660.

30. Wang X, Ye Y, Gong H, Wu J, Yuan J, Wang S et al. The effects of different angiotensin II type 1 receptor blockers on the regulation of the ACE-AngII-AT1 and ACE2-Ang(1-7)-Mas axes in pressure overload-induced cardiac remodeling in male mice. J Mol Cell Cardiol. 2016;97:180-90. doi: 10.1016/j.yjmcc.2016.05.012.

31. Ferrario C, Jessup J, Chappell M, Averill D, Brosnihan K, Tallant E et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation. 2005;111(20):2605-10. doi: 10.1161/CIRCULATIONAHA.104.510461.

32. Soler M, Ye M, Wysocki J, William J, Lloveras J, Batlle D. Localization of ACE2 in the renal vasculature: amplification by angiotensin II type 1 receptor blockade using telmisartan. Am J Physiol Renal Physiol. 2009;296:F398-405. doi: 10.1152/ajprenal.90488.2008.

33. Rico-Mesa J, White A, Anderson A. Outcomes in patients with COVID-19 infection taking ACEI/ARB. Curr. Cardiol. Rep. 2020;22(5):31. doi: 10.1007/s11886-020-01291-4.

34. Puskarich M, Cummins N, Ingraham N, Wacker D, Reilkoff R, Driver B et al. A multi-center phase II randomized clinical trial of losartan on symptomatic outpatients with COVID-19. EClinicalMedicine. 2021;37:100957. doi: 10.1016/j.eclinm.2021.100957.

35. Tornling G, Batta R, Porter J, Williams B, Bengtsson T, Parmar K et al. Seven days treatment with the angiotensin II type 2 receptor agonist C21 in hospitalized COVID-19 patients; a placebo-controlled randomised multi-centre double-blind phase 2 trial. EClinicalMedicine. 2021;41:101152. doi: 10.1016/j.eclinm.2021.101152.

36. Циберкин А.И., Головатюк К.А., Быкова Е.С., Андреева А.Т., Вашукова М.А., Цой У.А., Каронова Т.Л. Гипокалиемия и активность ренин‑ангиотензин‑альдостероновой системы у больных COVID‑19. Артериальная гипертензия. 2021;27(4):457–463. doi:10.18705/1607-419X-2021-27-4-457-463.

37. Zhang X, Li S, Niu S. ACE2 and COVID-19 and the resulting ARDS. Postgrad Med J. 2020 Jul;96(1137):403-407. doi: 10.1136/postgradmedj-2020-137935.

38. Visseren F, Mach F, Smulders Y, Carballo D, Koskinas K, Bäck M et al. ESC National Cardiac Societies; ESC Scientific Document Group. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021;42(34):3227-3337. doi: 10.1093/eurheartj/ehab484.

39. Perlot T, Penninger JM. ACE2 - from the renin-angiotensin system to gut microbiota and malnutrition. Microbes Infect. 2013 Nov;15(13):866-73. doi: 10.1016/j.micinf.2013.08.003.

40. Zhang H, Li H, Lyu J, Lei X, Li W, Wu G et al. Specific ACE2 expression in small intestinal enterocytes may cause gastrointestinal symptoms and injury after 2019-nCoV infection. Int J Infect Dis. 2020;96:19-24. doi: 10.1016/j.ijid.2020.04.027.

41. Camargo S, Singer D, Makrides V, Huggel K, Pos K, Wagner C et al. Tissue-specific amino acid transporter partners ACE2 and collectrin differentially interact with hartnup mutations. Gastroenterology. 2009;136(3):872-82. doi: 10.1053/j.gastro.2008.10.055.

42. Kowalczuk S, Bröer A, Tietze N, Vanslambrouck JM, Rasko JE, Bröer S. A protein complex in the brush-border membrane explains a Hartnup disorder allele. FASEB J. 2008 Aug;22(8):2880-7. doi: 10.1096/fj.08-107300.

43. Perrin-Cocon L, Aublin-Gex A, Sestito S, Shirey K, Patel M, André P et al. TLR4 antagonist FP7 inhibits LPS-induced cytokine production and glycolytic reprogramming in dendritic cells, and protects mice from lethal influenza infection. Sci Rep. 2017;7:40791. doi: 10.1038/srep40791.

44. Gribar S, Anand R, Sodhi C, Hackam D. The role of epithelial Toll-like receptor signaling in the pathogenesis of intestinal inflammation. J Leukoc Biol. 2008;83(3):493-8. doi: 10.1189/jlb.0607358.

45. Zuo T, Zhang F, Lui G, Yeoh Y, Li A, Zhan H et al. Alterations in Gut Microbiota of Patients With COVID-19 During Time of Hospitalization. Gastroenterology. 2020;159(3):944-955.e8. doi: 10.1053/j.gastro.2020.05.048.

46. Bosch B, van der Zee R, de Haan C, Rottier P. The coronavirus spike protein is a class I virus fusion protein: structural and functional characterization of the fusion core complex. J Virol. 2003;77(16):8801-11. doi: 10.1128/jvi.77.16.8801-8811.2003.

47. Coutard B, Valle C, de Lamballerie X, Canard B, Seidah N, Decroly E. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. Antiviral Res. 2020;176:104742. doi: 10.1016/j.antiviral.2020.104742.

48. Zhou P, Yang X, Wang X, Hu B, Zhang L, Zhang W et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270-273. doi: 10.1038/s41586-020-2012-7.

49. Wong S, Li W, Moore M, Choe H, Farzan M. A 193-amino acid fragment of the SARS coronavirus S protein efficiently binds angiotensin-converting enzyme 2. J Biol Chem. 2004 Jan 30;279(5):3197-201. doi: 10.1074/jbc.C300520200.

50. Heald-Sargent T, Gallagher T. Ready, set, fuse! The coronavirus spike protein and acquisition of fusion competence. Viruses. 2012;4(4):557-80. doi: 10.3390/v4040557.

51. Millet J, Whittaker G. Host cell proteases: Critical determinants of coronavirus tropism and pathogenesis. Virus Res. 2015;202:120-34. doi: 10.1016/j.virusres.2014.11.021.

52. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger 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):271-280.e8. doi: 10.1016/j.cell.2020.02.052.

53. Glowacka I, Bertram S, Müller M, Allen P, Soilleux E, Pfefferle S et al. Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response. J Virol. 2011;85(9):4122-34. doi: 10.1128/JVI.02232-10.

54. Böttcher E, Matrosovich T, Beyerle M, Klenk H, Garten W, Matrosovich M. Proteolytic activation of influenza viruses by serine proteases TMPRSS2 and HAT from human airway epithelium. J Virol. 2006;80(19):9896-8. doi: 10.1128/JVI.01118-06.

55. Hofmann H, Geier M, Marzi A, Krumbiegel M, Peipp M, Fey G et al. Susceptibility to SARS coronavirus S protein-driven infection correlates with expression of angiotensin converting enzyme 2 and infection can be blocked by soluble receptor. Biochem Biophys Res Commun. 2004;319(4):1216-21. doi: 10.1016/j.bbrc.2004.05.114.

56. Monteil V, Kwon H, Prado P, Hagelkrüys A, Wimmer R, Stahl M et al. Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2. Cell. 2020;181(4):905-913.e7. doi: 10.1016/j.cell.2020.04.004.

57. Lei C, Qian K, Li T, Zhang S, Fu W, Ding M et al. Neutralization of SARS-CoV-2 spike pseudotyped virus by recombinant ACE2-Ig. Nat Commun. 2020;11(1):2070. doi: 10.1038/s41467-020-16048-4.

58. Zhang G, Pomplun S, Loftis AR, et al. Investigation of ACE2 N-terminal fragments binding to SARS-CoV-2 Spike RBD. bioRxiv; 2020. [Preprint]. DOI: 10.1101/2020.03.19.999318.

59. Baum A, Fulton B, Wloga E, Copin R, Pascal K, Russo V et al. Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies. Science. 2020;369(6506):1014-1018. doi: 10.1126/science.abd0831.

60. Clinical Trial NCT04335136. Recombinant Human Angiotensin-converting Enzyme 2 (rhACE2) as a Treatment for Patients With COVID-19 (APN01-COVID-19). [Internet]. Available from: https://clinicaltrials.gov/ct2/show/NCT04335136.

61. Haschke M, Schuster M, Poglitsch M, Loibner H, Salzberg M, Bruggisser M et al. Pharmacokinetics and pharmacodynamics of recombinant human angiotensin-converting enzyme 2 in healthy human subjects. Clin Pharmacokinet. 2013;52(9):783-92. doi: 10.1007/s40262-013-0072-7.

62. Khan A, Benthin C, Zeno B, Albertson T, Boyd J, Christie J et al. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit Care. 2017;21(1):234. doi: 10.1186/s13054-017-1823-x.

63. Nicholls J, Peiris M. Good ACE, bad ACE do battle in lung injury, SARS. Nat Med. 2005;11(8):821-2. doi: 10.1038/nm0805-821.

64. McMillan P, Uhal BD. COVID-19-A theory of autoimmunity to ACE-2. MOJ Immunol. 2020;7(1):17-19.

65. Takahashi Y, Haga S, Ishizaka Y, Mimori A. Autoantibodies to angiotensin-converting enzyme 2 in patients with connective tissue diseases. Arthritis Res Ther. 2010;12(3):R85. doi: 10.1186/ar3012.

66. Richardson S, Hirsch J, Narasimhan M, Crawford J, McGinn T, Davidson K et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. 2020;323(20):2052-2059.

67. Danilov S, Muzykantov V, Martynov A, Atochina E, Sakharov I, Trakht I, Smirnov V. Lung is the target organ for a monoclonal antibody to angiotensin-converting enzyme. Lab Invest. 1991;64(1):118-24.

68. Camussi G, Biesecker G, Caldwell P, Biancone L, Andres G, Brentjens J. Role of the membrane attack complex of complement in lung injury mediated by antibodies to endothelium. Int Arch Allergy Immunol. 1993;102(3):216-23. doi: 10.1159/000236529.