Changes in the SARS-CoV-2 cellular receptor ACE2 levels in cardiovascular patients: a potential biomarker for the stratification of COVID-19 patients.
Angiotensin converting enzyme 2 (ACE2)
Cardiovascular disease
Heart failure
Hypertension
RAAS inhibitors
Renin-angiotensin-aldosterone system (RAAS)
SARS-CoV-2
Journal
GeroScience
ISSN: 2509-2723
Titre abrégé: Geroscience
Pays: Switzerland
ID NLM: 101686284
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
received:
08
06
2021
accepted:
22
09
2021
pubmed:
22
10
2021
medline:
23
11
2021
entrez:
21
10
2021
Statut:
ppublish
Résumé
Angiotensin-converting enzyme 2 (ACE2) is essential for SARS-CoV-2 cellular entry. Here we studied the effects of common comorbidities in severe COVID-19 on ACE2 expression. ACE2 levels (by enzyme activity and ELISA measurements) were determined in human serum, heart and lung samples from patients with hypertension (n = 540), heart transplantation (289) and thoracic surgery (n = 49). Healthy individuals (n = 46) represented the controls. Serum ACE2 activity was increased in hypertensive subjects (132%) and substantially elevated in end-stage heart failure patients (689%) and showed a strong negative correlation with the left ventricular ejection fraction. Serum ACE2 activity was higher in male (147%), overweight (122%), obese (126%) and elderly (115%) hypertensive patients. Primary lung cancer resulted in higher circulating ACE2 activity, without affecting ACE2 levels in the surrounding lung tissue. Male sex resulted in elevated serum ACE2 activities in patients with heart transplantation or thoracic surgery (146% and 150%, respectively). Left ventricular (tissular) ACE2 activity was unaffected by sex and was lower in overweight (67%), obese (62%) and older (73%) patients with end-stage heart failure. There was no correlation between serum and tissular (left ventricular or lung) ACE2 activities. Neither serum nor tissue (left ventricle or lung) ACE2 levels were affected by RAS inhibitory medications. Abandoning of ACEi treatment (non-compliance) resulted in elevated blood pressure without effects on circulating ACE2 activities. ACE2 levels associate with the severity of cardiovascular diseases, suggestive for a role of ACE2 in the pathomechanisms of cardiovascular diseases and providing a potential explanation for the higher mortality of COVID-19 among cardiovascular patients. Abandoning RAS inhibitory medication worsens the cardiovascular status without affecting circulating or tissue ACE2 levels.
Identifiants
pubmed: 34674152
doi: 10.1007/s11357-021-00467-2
pii: 10.1007/s11357-021-00467-2
pmc: PMC8529378
doi:
Substances chimiques
Biomarkers
0
ACE2 protein, human
EC 3.4.17.23
Angiotensin-Converting Enzyme 2
EC 3.4.17.23
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2289-2304Subventions
Organisme : European Union and the European Regional Development Fund
ID : GINOP-2.3.2-15-2016-00043
Organisme : European Union and the European Regional Development Fund
ID : GINOP-2.3.2-15-2016-00050
Organisme : National Research, Development and Innovation Fund of Hungary
ID : FK 128809
Organisme : National Research, Development and Innovation Fund of Hungary
ID : K134939
Organisme : National Research, Development and Innovation Fund of Hungary
ID : K 116940 and K 132623
Organisme : National Research, Development and Innovation Fund of Hungary
ID : NVKP_16-1-2016-0017 ('National Heart Program'
Organisme : National Research, Development and Innovation Fund of Hungary
ID : TKP2020-NKA-04
Organisme : Ministry for Innovation and Technology in Hungary
ID : Thematic Excellence Programme (2020-4.1.1.-TKP2020), Therapeutic Development and Bioimaging thematic programmes of the Semmelweis University
Informations de copyright
© 2021. The Author(s).
Références
Coronavirus Resource Center, Johns Hopkins University. https://coronavirus.jhu.edu/map.html . Accessed 7 May 202.
Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020. https://doi.org/10.1016/s2213-2600(20)30116-8 .
Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020. https://doi.org/10.1016/s2213-2600(20)30079-5 .
Zhang JJ, Dong X, Cao YY, Yuan YD, Yang YB, Yan YQ, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy. 2020. https://doi.org/10.1111/all.14238 .
Clark CE, McDonagh STJ, McManus RJ, Martin U. COVID-19 and hypertension: risks and management. A scientific statement on behalf of the British and Irish hypertension society. J Hum Hypertens. 2021;35(4):304–7. https://doi.org/10.1038/s41371-020-00451-x .
doi: 10.1038/s41371-020-00451-x
pubmed: 33483621
pmcid: 7821986
Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, et al. Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020;5(7):811–8. https://doi.org/10.1001/jamacardio.2020.1017 .
doi: 10.1001/jamacardio.2020.1017
pubmed: 32219356
Linschoten, Asselbergs FW. CAPACITY-COVID: a European registry to determine the role of cardiovascular disease in the COVID-19 pandemic. Eur Heart J. 2020. https://doi.org/10.1093/eurheartj/ehaa280 .
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. https://doi.org/10.1016/j.cell.2020.02.052 .
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. https://doi.org/10.1016/j.cell.2020.02.058 .
Jia H. Pulmonary angiotensin-converting enzyme 2 (ACE2) and inflammatory lung disease. Shock. 2016;46(3):239–48. https://doi.org/10.1097/shk.0000000000000633 .
doi: 10.1097/shk.0000000000000633
pubmed: 27082314
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.
doi: 10.1007/s00134-020-05985-9
Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res. 2020. https://doi.org/10.1002/ddr.21656 .
Rapid increase of a SARS-CoV-2 variant with multiple spike protein mutations observed in the United Kingdom. European Centre for Disease Prevention and Control, Stockholm. 2020. https://www.ecdc.europa.eu/sites/default/files/documents/SARS-CoV-2-variant-multiple-spike-protein-mutations-United-Kingdom.pdf . Accessed 20 Dec 2020.
Nagy B, Fejes Z, Szentkereszty Z, Sütő R, Várkonyi I, Ajzner É, et al. A dramatic rise in serum ACE2 activity in a critically ill COVID-19 patient. Int J Infect Dis. 2021;103:412–4. https://doi.org/10.1016/j.ijid.2020.11.184 .
doi: 10.1016/j.ijid.2020.11.184
pubmed: 33249290
Reindl-Schwaighofer R, Hodlmoser S, Eskandary F, Poglitsch M, Bonderman D, Strassl R, et al. ACE2 elevation in severe COVID-19. Am J Respir Crit Care Med. 2021;203(9):1191–6. https://doi.org/10.1164/rccm.202101-0142LE .
doi: 10.1164/rccm.202101-0142LE
pubmed: 33600742
pmcid: 8314901
Atlas SA. The renin-angiotensin aldosterone system: pathophysiological role and pharmacologic inhibition. J Manag Care Pharm. 2007;13(8 Suppl B):9–20. https://doi.org/10.18553/jmcp.2007.13.s8-b.9 .
doi: 10.18553/jmcp.2007.13.s8-b.9
pubmed: 17970613
Esler M, Esler D. Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic? J Hypertens. 2020;Publish Ahead of Print. https://doi.org/10.1097/hjh.0000000000002450 .
Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol. 2020. https://doi.org/10.1038/s41569-020-0360-5 .
Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19. N Engl J Med. 2020. https://doi.org/10.1056/NEJMsr2005760 .
Kuster GM, Pfister O, Burkard T, Zhou Q, Twerenbold R, Haaf P, et al. SARS-CoV2: should inhibitors of the renin-angiotensin system be withdrawn in patients with COVID-19? Eur Heart J. 2020. https://doi.org/10.1093/eurheartj/ehaa235 .
Ferrario CM, Jessup J, Chappell MC, Averill DB, Brosnihan KB, Tallant EA, 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. https://doi.org/10.1161/circulationaha.104.510461 .
doi: 10.1161/circulationaha.104.510461
pubmed: 15897343
Ishiyama Y, Gallagher PE, Averill DB, Tallant EA, Brosnihan KB, Ferrario CM. Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors. Hypertension. 2004;43(5):970–6. https://doi.org/10.1161/01.HYP.0000124667.34652.1a .
doi: 10.1161/01.HYP.0000124667.34652.1a
pubmed: 15007027
Position statement of the ESC Council on Hypertension on ACE-inhibitors and angiotensin receptor blockers. European Society of Cardiology. 2020. https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang . Accessed 19 Mar 2020.
Patients taking ACE-i and ARBs who contract COVID-19 should continue treatment, unless otherwise advised by their physician. American Heart Association. 2020. https://newsroom.heart.org/news/patients-taking-ace-i-and-arbs-who-contract-covid-19-should-continue-treatment-unless-otherwise-advised-by-their-physician . Accessed 19 Mar 2020.
Kreutz R, Algharably EAE, Azizi M, Dobrowolski P, Guzik T, Januszewicz A, et al. Hypertension, the renin-angiotensin system, and the risk of lower respiratory tract infections and lung injury: implications for COVID-19. Cardiovasc Res. 2020. https://doi.org/10.1093/cvr/cvaa097 .
Yanez ND, Weiss NS, Romand JA, Treggiari MM. COVID-19 mortality risk for older men and women. BMC Public Health. 2020;20(1):1742. https://doi.org/10.1186/s12889-020-09826-8 .
doi: 10.1186/s12889-020-09826-8
pubmed: 33213391
pmcid: 7675386
Sayour AA, Oláh A, Ruppert M, Barta BA, Horváth EM, Benke K, et al. Characterization of left ventricular myocardial sodium-glucose cotransporter 1 expression in patients with end-stage heart failure. Cardiovasc Diabetol. 2020;19(1):159. https://doi.org/10.1186/s12933-020-01141-1 .
doi: 10.1186/s12933-020-01141-1
pubmed: 32998746
pmcid: 7528261
Uri K, Fagyas M, Kertesz A, Borbely A, Jenei C, Bene O, et al. Circulating ACE2 activity correlates with cardiovascular disease development. J Renin-Angiotensin-Aldosterone Syst. 2016;17(4):1–11. https://doi.org/10.1177/1470320316668435 .
doi: 10.1177/1470320316668435
Uri K, Fagyas M, Manyine Siket I, Kertesz A, Csanadi Z, Sandorfi 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. https://doi.org/10.1371/journal.pone.0087845 .
doi: 10.1371/journal.pone.0087845
pubmed: 24691269
pmcid: 3972189
Fagyas M, Uri K, Siket IM, Darago A, Boczan J, Banyai E, et al. New perspectives in the renin-angiotensin-aldosterone system (RAAS) I: endogenous angiotensin converting enzyme (ACE) inhibition. PLoS One. 2014;9(4):e87843.
doi: 10.1371/journal.pone.0087843
Fagyas M, Uri K, Siket IM, Fulop GA, Csato V, Darago A, et al. New perspectives in the renin-angiotensin-aldosterone system (RAAS) II: albumin suppresses angiotensin converting enzyme (ACE) activity in human. PLoS One. 2014;9(4):e87844.
doi: 10.1371/journal.pone.0087844
Tóth A, Fagyas M, Papp Z, Édes I. inventors; University of Debrecen, assignee. Hungary: Dilution based inhibition assay; 2012.
Luan J, Jin X, Lu Y, Zhang L. SARS-CoV-2 spike protein favors ACE2 from Bovidae and Cricetidae. J Med Virol. 2020. https://doi.org/10.1002/jmv.25817 .
Wallentin L, Lindbäck J, Eriksson N, Hijazi Z, Eikelboom JW, Ezekowitz MD, et al. Angiotensin-converting enzyme 2 (ACE2) levels in relation to risk factors for COVID-19 in two large cohorts of patients with atrial fibrillation. Eur Heart J. 2020. https://doi.org/10.1093/eurheartj/ehaa697 .
Sama IE, Ravera A, Santema BT, van Goor H, Ter Maaten JM, Cleland JGF, et al. Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors. Eur Heart J. 2020;41(19):1810–7. https://doi.org/10.1093/eurheartj/ehaa373 .
doi: 10.1093/eurheartj/ehaa373
pubmed: 32388565
pmcid: 7239195
Assarsson E, Lundberg M, Holmquist G, Björkesten J, Thorsen SB, Ekman D, et al. Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability. PLoS One. 2014;9(4):e95192. https://doi.org/10.1371/journal.pone.0095192 .
doi: 10.1371/journal.pone.0095192
pubmed: 24755770
pmcid: 3995906
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 .
doi: 10.1038/nature00786
pubmed: 12075344
Gurley SB, Allred A, Le TH, Griffiths R, Mao L, Philip N, et al. Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice. J Clin Invest. 2006;116(8):2218–25. https://doi.org/10.1172/JCI16980 .
doi: 10.1172/JCI16980
pubmed: 16878172
pmcid: 1518789
Fagyas M, Kertész A, Siket IM, Bánhegyi V, Kracskó B, Szegedi A, et al. Level of the SARS-CoV-2 receptor ACE2 activity is highly elevated in old-aged patients with aortic stenosis: implications for ACE2 as a biomarker for the severity of COVID-19. GeroScience. 2021;43(1):19–29. https://doi.org/10.1007/s11357-020-00300-2 .
doi: 10.1007/s11357-020-00300-2
pubmed: 33469835
pmcid: 7815502
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. https://doi.org/10.1093/eurheartj/ehaa311 .
Kovács Á, Fülöp GÁ, Kovács A, Csípő T, Bódi B, Priksz D, et al. Renin overexpression leads to increased titin-based stiffness contributing to diastolic dysfunction in hypertensive mRen2 rats. Am J Phys Heart Circ Phys. 2016;310(11):H1671–H82. https://doi.org/10.1152/ajpheart.00842.2015 .
doi: 10.1152/ajpheart.00842.2015
Jia HP, Look DC, Tan P, Shi L, Hickey M, Gakhar L, et al. Ectodomain shedding of angiotensin converting enzyme 2 in human airway epithelia. Am J Phys Lung Cell Mol Phys. 2009;297(1):L84–96. https://doi.org/10.1152/ajplung.00071.2009 .
doi: 10.1152/ajplung.00071.2009
Mukerjee S, Gao H, Xu J, Sato R, Zsombok A, Lazartigues E. ACE2 and ADAM17 interaction regulates the activity of Presympathetic neurons. Hypertension. 2019;74(5):1181–91. https://doi.org/10.1161/HYPERTENSIONAHA.119.13133 .
doi: 10.1161/HYPERTENSIONAHA.119.13133
pubmed: 31564162
Chodavarapu H, Pedersen K, Lazartigues E. The ACE2 sheddase, ADAM17, is up-regulated in diabetic db/db mice. FASEB J. 2015;29(S1):997.1. https://doi.org/10.1096/fasebj.29.1_supplement.997.1 .
doi: 10.1096/fasebj.29.1_supplement.997.1
Zhang L, Han X, Shi Y. Comparative analysis of SARS-CoV-2 receptor ACE2 expression in multiple solid tumors and matched non-diseased tissues. Infect Genet Evol : J Mol Epidemiol Evol Gen Infect Dis. 2020;85:104428. https://doi.org/10.1016/j.meegid.2020.104428 .
doi: 10.1016/j.meegid.2020.104428
Chen Y, Guo Y, Pan Y, Zhao ZJ. Structure analysis of the receptor binding of 2019-nCoV. Biochem Biophys Res Commun. 2020. https://doi.org/10.1016/j.bbrc.2020.02.071 .
Hui DSC, Zumla A. Severe acute respiratory syndrome: historical, epidemiologic, and clinical features. Infect Dis Clin N Am. 2019;33(4):869–89. https://doi.org/10.1016/j.idc.2019.07.001 .
doi: 10.1016/j.idc.2019.07.001
Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med. 2020;382(10):929–36. https://doi.org/10.1056/NEJMoa2001191 .
doi: 10.1056/NEJMoa2001191
pubmed: 7092802
pmcid: 7092802
Gagliardi I, Patella G, Michael A, Serra R, Provenzano M, Andreucci M. COVID-19 and the kidney: from epidemiology to clinical practice. J Clin Med. 2020;9(8):2506. https://doi.org/10.3390/jcm9082506 .
doi: 10.3390/jcm9082506
pmcid: 7464116
Ng JH, Bijol V, Sparks MA, Sise ME, Izzedine H, Jhaveri KD. Pathophysiology and pathology of acute kidney injury in patients with COVID-19. Adv Chronic Kidney Dis. 2020;27(5):365–76. https://doi.org/10.1053/j.ackd.2020.09.003 .
doi: 10.1053/j.ackd.2020.09.003
pubmed: 33308501
pmcid: 7574722
Tai W, He L, Zhang X, Pu J, Voronin D, Jiang S, et al. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cell Mol Immunol. 2020. https://doi.org/10.1038/s41423-020-0400-4 .