Glycated ACE2 Reduces Anti-remodeling Effects of Renin-angiotensin System Inhibition in Human Diabetic Hearts

Overview

Journal Cardiovasc Diabetol

Publisher Biomed Central

Specialties Cardiology & Vascular Diseases
Endocrinology

Date 2022 Aug 5

PMID 35932065

Authors

Raffaele Marfella

Nunzia DOnofrio

Gelsomina Mansueto

Vincenzo Grimaldi

Maria Consiglia Trotta

Celestino Sardu

Ferdinando Carlo Sasso

Lucia Scisciola

Cristiano Amarelli

Salvatore Esposito

Michele DAmico

Paolo Golino

Marisa De Feo

Giuseppe Signoriello

Pasquale Paolisso

Emanuele Gallinoro

Marc Vanderheyden

Ciro Maiello

Maria Luisa Balestrieri

Emanuele Barbato

Claudio Napoli

Giuseppe Paolisso

Affiliations

Soon will be listed here.

Abstract

Background: High glycated-hemoglobin (HbA1c) levels correlated with an elevated risk of adverse cardiovascular outcomes despite renin-angiotensin system (RAS) inhibition in type-2 diabetic (T2DM) patients with reduced ejection fraction. Using the routine biopsies of non-T2DM heart transplanted (HTX) in T2DM recipients, we evaluated whether the diabetic milieu modulates glycosylated ACE2 (GlycACE2) levels in cardiomyocytes, known to be affected by non-enzymatic glycosylation, and the relationship with glycemic control.

Objectives: We investigated the possible effects of GlycACE2 on the anti-remodeling pathways of the RAS inhibitors by evaluating the levels of Angiotensin (Ang) 1-9, Ang 1-7, and Mas receptor (MasR), Nuclear-factor of activated T-cells (NFAT), and fibrosis in human hearts.

Methods: We evaluated 197 first HTX recipients (107 non-T2DM, 90 T2DM). All patients were treated with angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) at hospital discharge. Patients underwent clinical evaluation (metabolic status, echocardiography, coronary CT-angiography, and endomyocardial biopsies). Biopsies were used to evaluate ACE2, GlycACE2, Ang 1-9, Ang 1-7, MasR, NAFT, and fibrosis.

Results: GlycACE2 was higher in T2DM compared tonon-T2DM cardiomyocytes. Moreover, reduced expressions of Ang 1-9, Ang 1-7, and MasR were observed, suggesting impaired effects of RAS-inhibition in diabetic hearts. Accordingly, biopsies from T2DM recipients showed higher fibrosis than those from non-T2DM recipients. Notably, the expression of GlycACE2 in heart biopsies was strongly dependent on glycemic control, as reflected by the correlation between mean plasma HbA1c, evaluated quarterly during the 12-month follow-up, and GlycACE2 expression.

Conclusion: Poor glycemic control, favoring GlycACE2, may attenuate the cardioprotective effects of RAS-inhibition. However, the achievement of tight glycemic control normalizes the anti-remodeling effects of RAS-inhibition.

Trial Registration: https://clinicaltrials.gov/ NCT03546062.

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References

Selvin E, Marinopoulos S, Berkenblit G, Rami T, Brancati F, Powe N . Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med. 2004; 141(6):421-31. DOI: 10.7326/0003-4819-141-6-200409210-00007. View

Ichida M, Finkel T . Ras regulates NFAT3 activity in cardiac myocytes. J Biol Chem. 2000; 276(5):3524-30. DOI: 10.1074/jbc.M004275200. View

Solomon S, St John Sutton M, Lamas G, Plappert T, Rouleau J, Skali H . Ventricular remodeling does not accompany the development of heart failure in diabetic patients after myocardial infarction. Circulation. 2002; 106(10):1251-5. DOI: 10.1161/01.cir.0000032313.82552.e3. View

Mechanick J, Farkouh M, Newman J, Garvey W . Cardiometabolic-Based Chronic Disease, Adiposity and Dysglycemia Drivers: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020; 75(5):525-538. PMC: 7187687. DOI: 10.1016/j.jacc.2019.11.044. View

Asadipooya K, Uy E . Advanced Glycation End Products (AGEs), Receptor for AGEs, Diabetes, and Bone: Review of the Literature. J Endocr Soc. 2019; 3(10):1799-1818. PMC: 6734192. DOI: 10.1210/js.2019-00160. View

Patel V, Bodiga S, Basu R, Das S, Wang W, Wang Z . Loss of angiotensin-converting enzyme-2 exacerbates diabetic cardiovascular complications and leads to systolic and vascular dysfunction: a critical role of the angiotensin II/AT1 receptor axis. Circ Res. 2012; 110(10):1322-35. PMC: 3746191. DOI: 10.1161/CIRCRESAHA.112.268029. View

Kristensen S, Preiss D, Jhund P, Squire I, Silva Cardoso J, Merkely B . Risk Related to Pre-Diabetes Mellitus and Diabetes Mellitus in Heart Failure With Reduced Ejection Fraction: Insights From Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial. Circ Heart Fail. 2016; 9(1). PMC: 4718182. DOI: 10.1161/CIRCHEARTFAILURE.115.002560. View

. 2. Classification and Diagnosis of Diabetes: . Diabetes Care. 2017; 41(Suppl 1):S13-S27. DOI: 10.2337/dc18-S002. View

Dong B, Yu Q, Dai H, Gao Y, Zhou Z, Zhang L . Angiotensin-converting enzyme-2 overexpression improves left ventricular remodeling and function in a rat model of diabetic cardiomyopathy. J Am Coll Cardiol. 2012; 59(8):739-47. DOI: 10.1016/j.jacc.2011.09.071. View

10.

Chen J, Lin X, Bu C, Zhang X . Role of advanced glycation end products in mobility and considerations in possible dietary and nutritional intervention strategies. Nutr Metab (Lond). 2018; 15:72. PMC: 6180645. DOI: 10.1186/s12986-018-0306-7. View

11.

Marfella R, Amarelli C, Cacciatore F, Balestrieri M, Mansueto G, DOnofrio N . Lipid Accumulation in Hearts Transplanted From Nondiabetic Donors to Diabetic Recipients. J Am Coll Cardiol. 2020; 75(11):1249-1262. DOI: 10.1016/j.jacc.2020.01.018. View

12.

Goldin A, Beckman J, Schmidt A, Creager M . Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation. 2006; 114(6):597-605. DOI: 10.1161/CIRCULATIONAHA.106.621854. View

13.

Nishikawa T, Edelstein D, Du X, Yamagishi S, Matsumura T, Kaneda Y . Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000; 404(6779):787-90. DOI: 10.1038/35008121. View

14.

Bohm M, Pogue J, Kindermann I, Poss J, Koon T, Yusuf S . Effect of comorbidities on outcomes and angiotensin converting enzyme inhibitor effects in patients with predominantly left ventricular dysfunction and heart failure. Eur J Heart Fail. 2014; 16(3):325-33. DOI: 10.1002/ejhf.23. View

15.

Galie N, Humbert M, Vachiery J, Gibbs S, Lang I, Torbicki A . 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):.... Eur Heart J. 2015; 37(1):67-119. DOI: 10.1093/eurheartj/ehv317. View

16.

Jia G, Hill M, Sowers J . Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity. Circ Res. 2018; 122(4):624-638. PMC: 5819359. DOI: 10.1161/CIRCRESAHA.117.311586. View

17.

Badano L, Miglioranza M, Edvardsen T, Colafranceschi A, Muraru D, Bacal F . European Association of Cardiovascular Imaging/Cardiovascular Imaging Department of the Brazilian Society of Cardiology recommendations for the use of cardiac imaging to assess and follow patients after heart transplantation. Eur Heart J Cardiovasc Imaging. 2015; 16(9):919-48. DOI: 10.1093/ehjci/jev139. View

18.

Ryden L, Armstrong P, Cleland J, Horowitz J, Massie B, Packer M . Efficacy and safety of high-dose lisinopril in chronic heart failure patients at high cardiovascular risk, including those with diabetes mellitus. Results from the ATLAS trial. Eur Heart J. 2000; 21(23):1967-78. DOI: 10.1053/euhj.2000.2311. View

19.

Hao P, Yang J, Liu Y, Zhang M, Zhang K, Gao F . Combination of angiotensin-(1-7) with perindopril is better than single therapy in ameliorating diabetic cardiomyopathy. Sci Rep. 2015; 5:8794. PMC: 4350094. DOI: 10.1038/srep08794. View

20.

Mori J, Patel V, Alrob O, Basu R, Altamimi T, DesAulniers J . Angiotensin 1-7 ameliorates diabetic cardiomyopathy and diastolic dysfunction in db/db mice by reducing lipotoxicity and inflammation. Circ Heart Fail. 2014; 7(2):327-39. DOI: 10.1161/CIRCHEARTFAILURE.113.000672. View