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Endocrine, Metabolic & Immune Disorders - Drug Targets

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ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

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Meta-Analysis

The Role of Soluble ACE2 as a Prognostic Marker in Severe COVID-19: A Brief Meta-Analysis

Author(s): Nadereh Naderi and Mahsa Rahimzadeh*

Volume 23, Issue 1, 2023

Published on: 07 October, 2022

Page: [70 - 76] Pages: 7

DOI: 10.2174/1871530322666220623121922

Price: $65

Abstract

Background: The recently emerged novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has posed a serious threat to public health, and there is an urgent need to establish tools that can aid the clinician in the evaluation and management of highrisk patients. This meta-analysis aimed to investigate the potential of sACE2 (soluble angiotensinconverting enzyme 2) as a prognostic biomarker in COVID-19.

Methods: A comprehensive search of PubMed/MEDLINE, Cochrane, and Google Scholar, was performed until May 26, 2021. Data extraction and quality assessment of the study were independently conducted by the authors. Finally, 6 studies were included in this meta-analysis.

Results: ACE-2 serum or plasma levels were compared between COVID-19 patients and healthy controls. ACE-2 level was not significantly different between severe COVID-19 patients and healthy controls (SMD = 1.2; 95% CI: -1.3-1.5; P = 0.86), severe and non-severe COVID-19 patients (SMD = 0.3; 95% CI: -0.06-0.7; P = 0.1), and severe COVID-19 patients and healthy controls (SMD = 0.6; 95% CI: -1.1-2.3; P = 0.5).

Conclusions:We cautiously propose that circulating levels of ACE2 cannot be used as a biomarker to assess disease severity in COVID-19 patients.

Keywords: COVID-19, angiotensin-converting enzyme 2, ACE2, biomarkers.

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Graphical Abstract

[1]
Huang, Y.; Yang, C.; Xu, X.F.; Xu, W.; Liu, S.W. Structural and functional properties of SARS-CoV-2 spike protein: Potential antivirus drug development for COVID-19. Acta Pharmacol. Sin., 2020, 41(9), 1141-1149.
[http://dx.doi.org/10.1038/s41401-020-0485-4] [PMID: 32747721]
[2]
Gagliardi, M.C.; Tieri, P.; Ortona, E.; Ruggieri, A. ACE2 expression and sex disparity in COVID-19. Cell Death Discov., 2020, 6(1), 37.
[http://dx.doi.org/10.1038/s41420-020-0276-1] [PMID: 32499922]
[3]
Shastri, A.; Wheat, J.; Agrawal, S.; Chaterjee, N.; Pradhan, K.; Goldfinger, M.; Kornblum, N.; Steidl, U.; Verma, A.; Shastri, J. Delayed clearance of SARS-CoV2 in male compared to female patients: High ACE2 expression in testes suggests possible existence of gender-specific viral reservoirs. MedRxiv, 2020.
[http://dx.doi.org/10.1101/2020.04.16.20060566]
[4]
Baker, S.A.; Kwok, S.; Berry, G.J.; Montine, T.J. Angiotensin-Converting Enzyme 2 (ACE2) expression increases with age in patients requiring mechanical ventilation. PLoS One, 2021, 16(2), e0247060.
[http://dx.doi.org/10.1371/journal.pone.0247060] [PMID: 33592054]
[5]
Yeung, M.L.; Teng, J.L.L.; Jia, L.; Zhang, C.; Huang, C.; Cai, J-P.; Zhou, R.; Chan, K-H.; Zhao, H.; Zhu, L. Soluble ACE2-mediated cell entry of SARS-CoV-2 via interaction with proteins related to the renin-angiotensin system. Cell, 2021, 184(8), 2212-2228.
[http://dx.doi.org/10.1016/j.cell.2021.02.053]
[6]
Patel, V.B.; Zhong, J.C.; Grant, M.B.; Oudit, G.Y. Role of the ACE2/angiotensin 1–7 axis of the renin–angiotensin system in heart failure. Circ. Res., 2016, 118(8), 1313-1326.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.307708] [PMID: 27081112]
[7]
Hasegawa, H.; Komuro, I. The progress of the study of RAAS. Jpn. J. Clin. Med., 2009, 67(4), 655-661.
[PMID: 19348224]
[8]
Benigni, A.; Cassis, P.; Remuzzi, G. Angiotensin II revisited: New roles in inflammation, immunology and aging. EMBO Mol. Med., 2010, 2(7), 247-257.
[http://dx.doi.org/10.1002/emmm.201000080] [PMID: 20597104]
[9]
Kuba, K.; Imai, Y.; Rao, S.; Gao, H.; Guo, F.; Guan, B.; Huan, Y.; Yang, P.; Zhang, Y.; Deng, W.; Bao, L.; Zhang, B.; Liu, G.; Wang, Z.; Chappell, M.; Liu, Y.; Zheng, D.; Leibbrandt, A.; Wada, T.; Slutsky, A.S.; Liu, D.; Qin, C.; Jiang, C.; Penninger, J.M. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat. Med., 2005, 11(8), 875-879.
[http://dx.doi.org/10.1038/nm1267] [PMID: 16007097]
[10]
Lambert, D.W.; Yarski, M.; Warner, F.J.; Thornhill, P.; Parkin, E.T.; Smith, A.I.; Hooper, N.M.; Turner, A.J. 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). J. Biol. Chem., 2005, 280(34), 30113-30119.
[http://dx.doi.org/10.1074/jbc.M505111200] [PMID: 15983030]
[11]
Rice, G.I.; Jones, A.L.; Grant, P.J.; Carter, A.M.; Turner, A.J.; Hooper, N.M. Circulating activities of angiotensin-converting enzyme, its homolog, angiotensin-converting enzyme 2, and neprilysin in a family study. Hypertension, 2006, 48(5), 914-920.
[http://dx.doi.org/10.1161/01.HYP.0000244543.91937.79] [PMID: 17000927]
[12]
Li, W.; Moore, M.J.; Vasilieva, N.; Sui, J.; Wong, S.K.; Berne, M.A.; Somasundaran, M.; Sullivan, J.L.; Luzuriaga, K.; Greenough, T.C.; Choe, H.; Farzan, M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature, 2003, 426(6965), 450-454.
[http://dx.doi.org/10.1038/nature02145] [PMID: 14647384]
[13]
Shao, Z.; Schuster, A.; Borowski, A.G.; Thakur, A.; Li, L.; Wilson Tang, W.H. Soluble angiotensin converting enzyme 2 levels in chronic heart failure is associated with decreased exercise capacity and increased oxidative stress-mediated endothelial dysfunction. Transl. Res., 2019, 212, 80-88.
[http://dx.doi.org/10.1016/j.trsl.2019.06.004] [PMID: 31323221]
[14]
Wang, K.; Gheblawi, M.; Oudit, G.Y. Angiotensin converting enzyme 2: A double-edged sword. Circulation, 2020, 142(5), 426-428.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047049] [PMID: 32213097]
[15]
Úri, K.; Fagyas, M.; Mányiné Siket, I.; Kertész, A.; Csanádi, Z.; Sándorfi, G.; Clemens, M.; Fedor, R.; Papp, Z.;Édes, I.; Tóth, A.; Lizanecz, E. 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.
[http://dx.doi.org/10.1371/journal.pone.0087845] [PMID: 24691269]
[16]
Kornilov, S.A.; Lucas, I.; Jade, K.; Dai, C.L.; Lovejoy, J.C.; Magis, A.T. Plasma levels of soluble ACE2are associated with sex, Metabolic Syndrome, and its biomarkers in a large cohort, pointing to a possible mechanism for increased severity in COVID-19. Crit. Care, 2020, 24(1), 452.
[http://dx.doi.org/10.1186/s13054-020-03141-9] [PMID: 32698840]
[17]
van Lier, D.; Kox, M.; Santos, K.; van der Hoeven, H.; Pillay, J.; Pickkers, P. Increased blood angiotensin converting enzyme 2 activity in critically ill COVID-19 patients. ERJ Open Res., 2021, 7(1), 00848-02020.
[http://dx.doi.org/10.1183/23120541.00848-2020] [PMID: 33738305]
[18]
Rojas, M.; Acosta-Ampudia, Y.; Monsalve, D.M. Ramírez-Santana, C.; Anaya, J.M. How important is the assessment of soluble ACE-2 in COVID-19? Am. J. Hypertens., 2021, 34(3), 296-297.
[http://dx.doi.org/10.1093/ajh/hpaa178] [PMID: 33156903]
[19]
Zhang, Y.; Sun, Y.; Liu, K.; Alolga, R.N.; Xu, X.; Feng, G.; Xiao, P. Low plasma angiotensin-converting enzyme 2 level in diabetics increases the risk of severe COVID-19 infection. Aging (Albany NY), 2021, 13(9), 12301-12307.
[http://dx.doi.org/10.18632/aging.202967] [PMID: 33962399]
[20]
Reindl-Schwaighofer, R. Hödlmoser, S.; Eskandary, F.; Poglitsch, M.; Bonderman, D.; Strassl, R.; Aberle, J.H.; Oberbauer, R.; Zoufaly, A.; Hecking, M. ACE2 elevation in severe COVID-19. Am. J. Respir. Crit. Care Med., 2021, 203(9), 1191-1196.
[http://dx.doi.org/10.1164/rccm.202101-0142LE] [PMID: 33600742]
[21]
Rahman, M.M.; Hasan, M.; Ahmed, A. Potential detrimental role of soluble ACE2 in severe COVID-19 comorbid patients. Rev. Med. Virol., 2021, 31(5), 1-12.
[http://dx.doi.org/10.1002/rmv.2213] [PMID: 33426683]
[22]
Hozo, S.P.; Djulbegovic, B.; Hozo, I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med. Res. Methodol., 2005, 5(1), 13.
[http://dx.doi.org/10.1186/1471-2288-5-13] [PMID: 15840177]
[23]
Lipsey, M.W.; Wilson, D.B. Practical Meta-Analysis; SAGE Publications, Inc.: Thousand Oaks, California, 2001.
[24]
Kragstrup, T.W.; Singh, H.S.; Grundberg, I.; Nielsen, A.L.; Rivellese, F.; Mehta, A.; Goldberg, M.B.; Filbin, M.; Qvist, P.; Bibby, B. M Plasma ACE2 levels predict outcome of COVID-19 in hospitalized patients. medRxiv, 2021.
[http://dx.doi.org/10.1101/2021.03.08.21252819]
[25]
Rieder, M.; Wirth, L.; Pollmeier, L.; Jeserich, M.; Goller, I.; Baldus, N.; Schmid, B.; Busch, H.J.; Hofmann, M.; Kern, W.; Bode, C.; Duerschmied, D.; Lother, A. Serum ACE2, angiotensin II, and aldosterone levels are unchanged in patients with COVID-19. Am. J. Hypertens., 2021, 34(3), 278-281.
[http://dx.doi.org/10.1093/ajh/hpaa169] [PMID: 33043967]
[26]
Feng, B.; Zhang, D.; Wang, Q.; Yu, F.; Zou, Q.; Xie, G.; Wang, R.; Yang, X.; Chen, W.; Lou, B.; Zheng, S.; Chen, Y. Effects of angiotensin II receptor blocker usage on viral load, antibody dynamics, and transcriptional characteristics among COVID-19 patients with hypertension. J. Zhejiang Univ. Sci. B, 2021, 22(4), 330-340.
[http://dx.doi.org/10.1631/jzus.B2000730] [PMID: 33835767]
[27]
Kintscher, U.; Slagman, A.; Domenig, O. Röhle, R.; Konietschke, F.; Poglitsch, M.; Möckel, M. Plasma angiotensin peptide profiling and ACE (Angiotensin-Converting Enzyme)-2 activity in COVID-19 patients treated with pharmacological blockers of the renin-angiotensin system. Hypertension, 2020, 76(5), e34-e36.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15841] [PMID: 32851897]
[28]
Al-Hakeim, H.; Al-Jassas, H.; Morris, G. Maes, M Increased angiotensin-converting enzyme 2, sRAGE and immune activation, but lowered calcium and magnesium in COVID-19: Association with chest CT abnormalities and lowered peripheral oxygen saturation. medRxiv, 2021.
[29]
Mohammadi, P.; Varpaei, H.A.; Seifi, A.; Miandoab, S.Z.; Beiranvand, S.; Mobaraki, S.; Mohammadi, M. Investigating the relationship between serum ACE 2 level and COVID-19 patients’ prognosis: A cross-sectional study. medRxiv, 2021.
[http://dx.doi.org/10.1101/2021.05.02.21256329]
[30]
Wang, J.; Zhao, H.; An, Y. ACE2 shedding and the role in covid-19. Front. Cell. Infect. Microbiol., 2022, 11, 789180.
[http://dx.doi.org/10.3389/fcimb.2021.789180] [PMID: 35096642]
[31]
Monteil, V.; Kwon, H.; Prado, P.; Hagelkrüys, A.; Wimmer, R.A.; Stahl, M.; Leopoldi, A.; Garreta, E.; Del Pozo, C.H.; Prosper, F. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell, 2020, 181(4), 905-913.
[http://dx.doi.org/10.1016/j.cell.2020.04.004]
[32]
Zoufaly, A.; Poglitsch, M.; Aberle, J.H.; Hoepler, W.; Seitz, T.; Traugott, M.; Grieb, A.; Pawelka, E.; Laferl, H.; Wenisch, C.; Neuhold, S.; Haider, D.; Stiasny, K.; Bergthaler, A.; Puchhammer-Stoeckl, E.; Mirazimi, A.; Montserrat, N.; Zhang, H.; Slutsky, A.S.; Penninger, J.M. Human recombinant soluble ACE2 in severe COVID-19. Lancet Respir. Med., 2020, 8(11), 1154-1158.
[http://dx.doi.org/10.1016/S2213-2600(20)30418-5] [PMID: 33131609]
[33]
García-Escobar. A.; Vera-Vera, S.; Jurado-Román, A.; Jiménez-Valero, S.; Galeote, G.; Moreno, R. Calcium signaling pathway is involved in the shedding of ACE2 catalytic ectodomain: New insights for clinical and therapeutic applications of ACE2 for COVID-19. Biomolecules, 2022, 12(1), 76.
[http://dx.doi.org/10.3390/biom12010076] [PMID: 35053224]
[34]
Heyman, S.N.; Kinaneh, S.; Abassi, Z. The duplicitous nature of ACE2 in COVID-19 disease. EBioMedicine, 2021, 67, 103356.
[http://dx.doi.org/10.1016/j.ebiom.2021.103356] [PMID: 33910120]
[35]
Heyman, S.N.; Walther, T.; Abassi, Z. Angiotensin-(1-7)-A potential remedy for AKI: Insights derived from the COVID-19 pandemic. J. Clin. Med., 2021, 10(6), 1200.
[http://dx.doi.org/10.3390/jcm10061200] [PMID: 33805760]
[36]
Gan, R.; Rosoman, N.P.; Henshaw, D.J.E.; Noble, E.P.; Georgius, P.; Sommerfeld, N. COVID-19 as a viral functional ACE2 deficiency disorder with ACE2 related multi-organ disease. Med. Hypotheses, 2020, 144, 110024.
[http://dx.doi.org/10.1016/j.mehy.2020.110024] [PMID: 32758871]
[37]
Dielis, A.W.; Smid, M.; Spronk, H.M.; Hamulyak, K.; Kroon, A.A.; ten Cate, H.; de Leeuw, P.W. The prothrombotic paradox of hypertension: Role of the renin-angiotensin and kallikrein-kinin systems. Hypertension, 2005, 46(6), 1236-1242.
[http://dx.doi.org/10.1161/01.HYP.0000193538.20705.23] [PMID: 16286563]
[38]
Zhang, L.; Zetter, M.A.; Guerra, E.C. Hernández, V.S.; Mahata, S.K.; Eiden, L.E. ACE2 in the second act of COVID-19 syndrome: Peptide dysregulation and possible correction with oestrogen. J. Neuroendocrinol., 2021, 33(2), e12935.
[http://dx.doi.org/10.1111/jne.12935] [PMID: 33462852]
[39]
Glowacka, I.; Bertram, S.; Herzog, P.; Pfefferle, S.; Steffen, I.; Muench, M.O.; Simmons, G.; Hofmann, H.; Kuri, T.; Weber, F.; Eichler, J.; Drosten, C. Pöhlmann, S. Differential downregulation of ACE2 by the spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus NL63. J. Virol., 2010, 84(2), 1198-1205.
[http://dx.doi.org/10.1128/JVI.01248-09] [PMID: 19864379]

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