Top

Published in:

Open Access 01-12-2021 | Autopsy | Original investigation

Glycated ACE2 receptor in diabetes: open door for SARS-COV-2 entry in cardiomyocyte

Authors: Nunzia D’Onofrio, Lucia Scisciola, Celestino Sardu, Maria Consiglia Trotta, Marisa De Feo, Ciro Maiello, Pasquale Mascolo, Francesco De Micco, Fabrizio Turriziani, Emilia Municinò, Pasquale Monetti, Antonio Lombardi, Maria Gaetana Napolitano, Federica Zito Marino, Andrea Ronchi, Vincenzo Grimaldi, Anca Hermenean, Maria Rosaria Rizzo, Michelangela Barbieri, Renato Franco, Carlo Pietro Campobasso, Claudio Napoli, Maurizio Municinò, Giuseppe Paolisso, Maria Luisa Balestrieri, Raffaele Marfella

Published in: Cardiovascular Diabetology | Issue 1/2021

Abstract

Rationale

About 50% of hospitalized coronavirus disease 2019 (COVID-19) patients with diabetes mellitus (DM) developed myocardial damage. The mechanisms of direct SARS-CoV-2 cardiomyocyte infection include viral invasion via ACE2-Spike glycoprotein-binding. In DM patients, the impact of glycation of ACE2 on cardiomyocyte invasion by SARS-CoV-2 can be of high importance.

Objective

To evaluate the presence of SARS-CoV-2 in cardiomyocytes from heart autopsy of DM cases compared to Non-DM; to investigate the role of DM in SARS-COV-2 entry in cardiomyocytes.

Methods and results

We evaluated consecutive autopsy cases, deceased for COVID-19, from Italy between Apr 30, 2020 and Jan 18, 2021. We evaluated SARS-CoV-2 in cardiomyocytes, expression of ACE2 (total and glycosylated form), and transmembrane protease serine protease-2 (TMPRSS2) protein. In order to study the role of diabetes on cardiomyocyte alterations, independently of COVID-19, we investigated ACE2, glycosylated ACE2, and TMPRSS2 proteins in cardiomyocytes from DM and Non-DM explanted-hearts. Finally, to investigate the effects of DM on ACE2 protein modification, an in vitro glycation study of recombinant human ACE2 (hACE2) was performed to evaluate the effects on binding to SARS-CoV-2 Spike protein. The authors included cardiac tissue from 97 autopsies. DM was diagnosed in 37 patients (38%). Fourth-seven out of 97 autopsies (48%) had SARS-CoV-2 RNA in cardiomyocytes. Thirty out of 37 DM autopsy cases (81%) and 17 out of 60 Non-DM autopsy cases (28%) had SARS-CoV-2 RNA in cardiomyocytes. Total ACE2, glycosylated ACE2, and TMPRSS2 protein expressions were higher in cardiomyocytes from autopsied and explanted hearts of DM than Non-DM. In vitro exposure of monomeric hACE2 to 120 mM glucose for 12 days led to non-enzymatic glycation of four lysine residues in the neck domain affecting the protein oligomerization.

Conclusions

The upregulation of ACE2 expression (total and glycosylated forms) in DM cardiomyocytes, along with non-enzymatic glycation, could increase the susceptibility to COVID-19 infection in DM patients by favouring the cellular entry of SARS-CoV2.

Available only for authorised users

Lala A, Johnson KW, Januzzi JL, et al. Prevalence and impact of myocardial injury in patients hospitalized with COVID-19 infection. J Am Coll Cardiol. 2020;76:533–46.CrossRefPubMedPubMedCentral

Shi S, Qin M, Cai Y, Liu T, et al. Characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease 2019. Eur Heart J. 2020;4:2070–9.CrossRef

Madjid M, Safavi-Naeini P, Solomon SD, Vardeny O. Potential effects of coronaviruses on the cardiovascular system: a review. JAMA Cardiol. 2020;5:831–40.CrossRefPubMed

Ceriello A, Standl E, Catrinoiu D, Itzhak B, Lalic NM, Rahelic D, Schnell O, Škrha J, Valensi P. Issues of cardiovascular risk management in people with diabetes in the COVID-19 era. Diabetes Care. 2020.

De Luca G, Cercek M, Jensen LO, et al. Impact of COVID-19 pandemic and diabetes on mechanical reperfusion in patients with STEMI: insights from the ISACS STEMI COVID 19 registry. Cardiovasc Diabetol. 2020;19:215. https://doi.org/10.1186/s12933-020-01196-0.CrossRefPubMedPubMedCentral

Sheshah E, Sabico S, Albakr RM, Sultan AA, Alghamdi KS, Madani KA, Alotair HA, Al-Daghri NM. Prevalence of diabetes, management and outcomes among Covid-19 adult patients admitted in a specialized tertiary hospital in Riyadh, Saudi Arabia. Diabetes Res Clin Pract. 2021;172:108538. https://doi.org/10.1016/j.diabres.2020.108538.CrossRefPubMed

Maddaloni E, D’Onofrio L, Alessandri F, Mignogna C, Leto G, Pascarella G, Mezzaroma I, Lichtner M, Pozzilli P, Agrò FE, Rocco M, Pugliese F, Lenzi A, Holman RR, Mastroianni CM, Buzzetti R, CoViDiab Study Group. Cardiometabolic multimorbidity is associated with a worse Covid-19 prognosis than individual cardiometabolic risk factors: a multicentre retrospective study (CoViDiab II). Cardiovasc Diabetol. 2020;19(1):164. https://doi.org/10.1186/s12933-020-01140-2.CrossRefPubMedPubMedCentral

Pretorius E, Venter C, Laubscher GJ et al. Prevalence of readily detected amyloid blood clots in ‘unclotted’ Type 2 diabetes mellitus and COVID-19 plasma: a preliminary report. Cardiovasc Diabetol 2020;193. https://doi.org/10.1186/s12933-020-01165-7.

Longo M, Caruso P, Maiorino MI, Bellastella G, Giugliano D, Esposito K. Treating type 2 diabetes in COVID-19 patients: the potential benefits of injective therapies. Cardiovasc Diabetol. 2020;19(1):115. https://doi.org/10.1186/s12933-020-01090-9.CrossRefPubMedPubMedCentral

10.

Ceriello A, Standl E, Catrinoiu D, Itzhak B, Lalic NM, Rahelic D, Schnell O, Škrha J, Valensi P. “Diabetes and Cardiovascular Disease (D&CVD)” Study Group of the European Association for the Study of Diabetes (EASD). Issues for the management of people with diabetes and COVID-19 in ICU. Cardiovasc Diabetol. 2020;19(1):114. https://doi.org/10.1186/s12933-020-01089-2.CrossRefPubMedPubMedCentral

11.

Ren H, Yang Y, Wang F, Yan Y, Shi X, Dong K, Yu X, Zhang S. Association of the insulin resistance marker TyG index with the severity and mortality of COVID-19. Cardiovasc Diabetol. 2020;19(1):58. https://doi.org/10.1186/s12933-020-01035-2.CrossRefPubMedPubMedCentral

12.

Sardu C, Gargiulo G, Esposito G, Paolisso G, Marfella R. Impact of diabetes mellitus on clinical outcomes in patients affected by Covid-19. Cardiovasc Diabetol. 2020;19(1):76. https://doi.org/10.1186/s12933-020-01047-y.CrossRefPubMedPubMedCentral

13.

Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395:507–13. https://doi.org/10.1016/S0140-6736(20)30211-7.CrossRefPubMedPubMedCentral

14.

Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Ericksen S, Schiergens TS, Herrler G, Wu N-W, Nitsche A, Müller MA, Drosten C, Pöhlmann S. 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. https://doi.org/10.1016/j.cell.2020.02.052.CrossRefPubMedPubMedCentral

15.

Shajahan, A, Archer-Hartmann, S, Supekar, NT, Gleinich, AS, Heiss, C, Azadi, P. Comprehensive characterization of N- and O-glycosylation of SARS-CoV-2 human receptor angiotensin converting enzyme 2. Glycobiology. 2020;cwaa101. https://doi.org/10.1093/glycob/cwaa101.

16.

Guo L, Bi W, Wang X, Xu W, Yan R, Zhang Y, Zhao K, Li Y, Zhang M, Cai X, Jiang S, Xie Y, Zhou Q, Lu L, Dang B. Engineered trimeric ACE2 binds viral spike protein and locks it in “Three-up” conformation to potently inhibit SARS-CoV-2 infection. Cell Res. 2021;31(1):98–100. https://doi.org/10.1038/s41422-020-00438-w.CrossRefPubMed

17.

Zhao P, Praissman JL, Grant OC, Cai Y, Xiao T, Rosenbalm KE, Aoki K, Kellman BP, Bridger R, Barouch DH, Brindley MA, Lewis NE, Tiemeyer M, Chen B, Woods RJ, Wellis L. Virus–receptor interactions of glycosylated SARS-CoV-2 spike and human ACE2 receptor. Cell Host Microbe. 2020;28(4):586–6016. https://doi.org/10.1016/j.chom.2020.08.004.CrossRefPubMedPubMedCentral

18.

Xiao T, Lu J, Zhang J, Johnson RI, McKay LGA, Storm N, Lavine CL, Peng H, Cai Y, Rits-Volloch S, Lu S, Quinlan BD, Farzan M, Seaman MS, Griffiths A, Chen B. A trimeric human angiotensin-converting enzyme 2 as an anti-SARS-CoV-2 agent. Nat Struct Mol Biol. 2021. https://doi.org/10.1038/s41594-020-00549-3.CrossRefPubMedPubMedCentral

19.

Chen Y, Liu Q, Guo D. Emerging coronaviruses: genome structure, replication, and pathogenesis. J Med Virol. 2020;92:418–23. https://doi.org/10.1002/jmv.25681.CrossRefPubMedPubMedCentral

20.

Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, Gong W, Liu X, Liang J, Zhao Q, Huang H, Yang B, Huang C. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol. 2020;5:802–10.CrossRefPubMedPubMedCentral

21.

Bulfamante GP, Perrucci GL, Falleni M, Sommariva E, Tosi D, Martinelli C, Songia P, Poggio P, Carugo S, Pompilio G. Evidence of SARS-CoV-2 transcriptional activity in cardiomyocytes of COVID-19 patients without clinical signs of cardiac involvement. Biomedicines. 2020;8(12):626. https://doi.org/10.3390/biomedicines8120626.CrossRefPubMedCentral

22.

Letarov AV, Babenko VV, Kulikov EE. Free SARS-CoV-2 spike protein S1 particles may play a role in the pathogenesis of COVID-19 infection. Biochemistry (Mosc). 2021;86(3):257–61. https://doi.org/10.1134/S0006297921030032.CrossRef

23.

Brufsky A. Hyperglycemia, hydroxychloroquine, and the COVID-19 pandemic. J Med Virol. 2020;92:770–5. https://doi.org/10.1002/jmv.25887.CrossRefPubMed

24.

Forbes M, Cooper ME. Mechanisms of diabetic complications. Physiol Rev. 2013;93:137–88.CrossRefPubMed

25.

Geuijen KPM, Oppers-Tiemissen C, Egging DF, Simons PJ, Boon L, Schasfoort RBM, Eppink MHM. Rapid screening of IgG quality attributes-effects on Fc receptor binding. FEBS Open Bio. 2017;7(10):1557–74. https://doi.org/10.1002/2211-5463.12283.CrossRefPubMedPubMedCentral

26.

Marfella R, Amarelli C, Cacciatore F, et al. Lipid accumulation in hearts transplanted from nondiabetic donors to diabetic recipients. J Am Coll Cardiol. 2020;75:1249–62.CrossRefPubMed

27.

Esposito S, Maiello C, Renzulli A, et al. Determinants and prognostic value of ischemic necrosis in early biopsies following heart transplant. Heart Vessels. 2000;15:167–71.CrossRefPubMed

28.

Cotrufo M, De Santo LS, Della Corte A, et al. Acute hemodynamic and functional effects of surgical ventricular restoration and heart transplantation in patients with ischemic dilated cardiomyopathy. J Thorac Cardiovasc Surg. 2008;135:1054–60.CrossRefPubMed

29.

American Diabetes Association. Classification and diagnosis of diabetes: standards of medical care in diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S13–27.CrossRef

30.

Galiè N, Humbert M, Vachiery JL, ESC Scientific Document Group. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37:67–119.CrossRefPubMed

31.

Corman VM, Landt O, Kaiser M, et al. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Euro Surveill. 2020;25:1804–6.

32.

Nicin L, Abplanalp WT, Mellentin H, et al. Cell type-specific expression of the putative SARS-CoV-2 receptor ACE2 in human hearts. Eur Heart J. 2020;41:1804–6.CrossRefPubMed

33.

Basso C, Leone O, Rizzo S, et al. Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study. Eur Heart J. 2020;41:3827–35.CrossRefPubMed

34.

Lindner D, Fitzek A, Bräuninger H, et al. Association of cardiac infection with SARS-CoV-2 in confirmed COVID-19 autopsy cases. JAMA Cardiol. 2021;5:1281–5.CrossRef

35.

Bojkova D, Wagner JUG, Shumliakivska M, et al. SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes. Cardiovasc Res. 2020;116:2207–15.CrossRefPubMed

36.

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

37.

Bernardi A, Huang Y, Harris B, Xiong Y, Nandi S, McDonald KA, Faller R. Development and simulation of fully glycosylated molecular models of ACE2-Fc fusion proteins and their interaction with the SARS-CoV-2 spike protein binding domain. PLoS ONE. 2020;8:e0237295. https://doi.org/10.1371/journal.pone.0237295.CrossRef

38.

Lan J, Ge J, Yu J, Shan S, Zhou H, Fan S, Zhang Q, Shi X, Wang Q, Zhang L, Wang X. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature. 2020;581:215–20. https://doi.org/10.1038/s41586-020-2180-5.CrossRefPubMed

39.

Chen L, Li X, Chen M, Feng Yi, 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(6):1097–100. https://doi.org/10.1093/cvr/cvaa078.CrossRefPubMed

40.

Goh SY, Cooper ME. Clinical review: the role of advanced glycation end products in progression and complications of diabetes. J Clin Endocrinol Metab. 2008;4:1143–52. https://doi.org/10.1210/jc.2007-1817.CrossRef

41.

Ravaioli S, Tebaldi M, Fonzi E, Angeli D, Mazza M, Nicolini F, Lucchesi A, Fanini F, Pirini F, Tumedei MM, Cerchione C, Viale P, Sambri V, Martinelli G, Bravaccini S. ACE2 and TMPRSS2 potential involvement in genetic susceptibility to SARS-COV-2 in cancer patients. Cell Transplant. 2020;29:96368–7209.CrossRef

42.

Glasgow A, Glasgow J, Limonta D, Solomon P, Lui I, Zhang Y, Nix MA, Rettko NJ, Zha S, Yamin R, Kao K, Rosenberg OS, Ravetch JV, Wiita AP, Leung KK, Lim SA, Zhou XX, Hobman TC, Kortemme T, Wells JA. Engineered ACE2 receptor traps potently neutralize SARS-CoV-2. Proc Natl Acad Sci USA. 2020;117(45):28046–55.CrossRefPubMedPubMedCentral

43.

Marfella R, Paolisso P, Sardu C, Bergamaschi L, D’Angelo EC, Barbieri M, Rizzo MR, Messina V, Maggi P, Coppola N, Pizzi C, Biffi M, Viale P, Galié N, Paolisso G. Negative impact of hyperglycaemia on tocilizumab therapy in Covid-19 patients. Diabetes Metab. 2020;46(5):403–5.CrossRefPubMedPubMedCentral

44.

Paolisso P, Bergamaschi L, D’Angelo EC, Donati F, Giannella M, Tedeschi S, Pascale R, Bartoletti M, Tesini G, Biffi M, Cosmi B, Pizzi C, Viale P, Galié N. Preliminary experience with low molecular weight heparin strategy in COVID-19 patients. Front Pharmacol. 2020;6(11):1124. https://doi.org/10.3389/fphar.2020.01124.PMID:32848743;PMCID:PMC7424043.CrossRef

45.

Bergamaschi L, D’Angelo EC, Paolisso P, Toniolo S, Fabrizio M, Angeli F, Donati F, Magnani I, Rinaldi A, Bartoli L, Chiti C, Biffi M, Pizzi C, Viale P, Galié N. The value of ECG changes in risk stratification of COVID-19 patients. Ann Noninvasive Electrocardiol. 2021;29:e12815. https://doi.org/10.1111/anec.12815.CrossRef

46.

Chung MK, Zidar DA, Bristow MR, Cameron SJ, Chan T, Harding CV 3rd, Kwon DH, Singh T, Tilton JC, Tsai EJ, Tucker NR, Barnard J, Loscalzo J. COVID-19 and cardiovascular disease: from bench to bedside. Circ Res. 2021;128(8):1214–36. https://doi.org/10.1161/CIRCRESAHA.121.317997.CrossRefPubMedPubMedCentral

Title: Glycated ACE2 receptor in diabetes: open door for SARS-COV-2 entry in cardiomyocyte
Authors: Nunzia D’Onofrio
Lucia Scisciola
Celestino Sardu
Maria Consiglia Trotta
Marisa De Feo
Ciro Maiello
Pasquale Mascolo
Francesco De Micco
Fabrizio Turriziani
Emilia Municinò
Pasquale Monetti
Antonio Lombardi
Maria Gaetana Napolitano
Federica Zito Marino
Andrea Ronchi
Vincenzo Grimaldi
Anca Hermenean
Maria Rosaria Rizzo
Michelangela Barbieri
Renato Franco
Carlo Pietro Campobasso
Claudio Napoli
Maurizio Municinò
Giuseppe Paolisso
Maria Luisa Balestrieri
Raffaele Marfella
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Autopsy
SARS-CoV-2
COVID-19
Diabetes
Published in: Cardiovascular Diabetology / Issue 1/2021
Electronic ISSN: 1475-2840
DOI: https://doi.org/10.1186/s12933-021-01286-7

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Rationale

Objective

Methods and results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2021

The association of hepatic steatosis and fibrosis with heart failure and mortality

The impact of central obesity on the risk of hospitalization or death due to heart failure in type 1 diabetes: a 16-year cohort study

Prognostic significance of diabetes mellitus in patients with atrial fibrillation

A cross sectional study to compare cardiac structure and diastolic function in adolescents and young adults with youth-onset type 1 and type 2 diabetes: The SEARCH for Diabetes in Youth Study

Impact of prior cerebrovascular disease and glucose status on incident cerebrovascular disease in Japanese

Association of TyG index and TG/HDL-C ratio with arterial stiffness progression in a non-normotensive population

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage