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

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.

Angiotensin I‐converting enzyme type 2 expression is increased in pancreatic islets of type 2 diabetic donors

“…Previous studies showed that other organs exposed to a diabetic milieu such as the lung, kidney and heart, showed the upregulation of ACE2, thus corroborating our findings in a different context. [42][43][44] Indeed, ACE2 expression was found to be increased in the bronchial epithelium and alveolar tissue of T2D donors and a linear relationship was detected between blood glucose levels and ACE2 expression in alveolar tissue. 42 In the heart tissue, ACE2 expression was significantly increased in cardiomyocytes of T2D patients with poor glycaemic control compared with ND patients and T2D patients with good glycaemic control.…”

“…42 In the heart tissue, ACE2 expression was significantly increased in cardiomyocytes of T2D patients with poor glycaemic control compared with ND patients and T2D patients with good glycaemic control. 43 In kidney organoids, ACE2 was expressed in tubular-like cells and an oscillatory glucose regimen induced the expression of ACE2. 44 Collectively, we can hypothesise that ACE2 expression is increased upon exposure to inflammation and/or high glucose or other stressors and that such chronic stress stimuli also exert their deleterious effect on beta-cells favouring the upregulation of ACE2.…”

“…[39][40][41] In T2D, ACE2 expression has been shown to be increased in several organs exposed to a diabetic milieu. [42][43][44] However, a systematic assessment of ACE2 expression in human pancreatic islets of T2D patients is still missing.…”

Prognostic value of elevated plasma angiotensin-converting enzyme 2 in cardiometabolic diseases: A review

“…ACE2 provided significant renal protection in patients with diabetes, while ACE2 deficiency aggravated diabetic kidney injury, rhACE2 has therapeutic effects in experimental Alport syndrome and diabetic nephropathy. [44,45] The results of Marfella et al [46] showed that high glucose environment was more conducive to the formation of glycosylated ACE2, and the expression of glycosylated ACE2 in cardiomyocytes was strongly correlated with blood glucose control. ACE2 and glycosylated ACE2 were lower in patients with good glycemic control (HbA1c < 7%) than in patients with poor glycemic control (HbA1c > 7%).…”

Reviewing the Modern Therapeutical Options and the Outcomes of Sacubitril/Valsartan in Heart Failure

“…It should be clarified that all patients followed a similar therapy with ACEI or ARB. The study evaluated the involvement of Ang 1–7 and Ang 1–9 molecules responsible for the antifibrotic effects at the cardiac myocyte level and observed that their levels are higher in patients without T2DM and in patients with better glycemic control [ 67 ].…”