Cardiovascular Diabetology (Aug 2022)

Glycated ACE2 reduces anti-remodeling effects of renin-angiotensin system inhibition in human diabetic hearts

  • Raffaele Marfella,
  • Nunzia D’Onofrio,
  • Gelsomina Mansueto,
  • Vincenzo Grimaldi,
  • Maria Consiglia Trotta,
  • Celestino Sardu,
  • Ferdinando Carlo Sasso,
  • Lucia Scisciola,
  • Cristiano Amarelli,
  • Salvatore Esposito,
  • Michele D’Amico,
  • Paolo Golino,
  • Marisa De Feo,
  • Giuseppe Signoriello,
  • Pasquale Paolisso,
  • Emanuele Gallinoro,
  • Marc Vanderheyden,
  • Ciro Maiello,
  • Maria Luisa Balestrieri,
  • Emanuele Barbato,
  • Claudio Napoli,
  • Giuseppe Paolisso

DOI
https://doi.org/10.1186/s12933-022-01573-x
Journal volume & issue
Vol. 21, no. 1
pp. 1 – 14

Abstract

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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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