Angiotensin-(1-9) attenuates diabetic cardiomyopathy by improving insulin resistance

Diabetic cardiomyopathy is a clinical condition of ventricular dysfunction, with obesity and insulin resistance as the primary risk factors. Under this condition, the heart encounters lipotoxicity, which impairs cardiac insulin sensitivity and leads to cardiomyopathy. Angiotensin-(1-9) is a peptide of the counter-regulatory axis of the renin-angiotensin system with cardioprotective effects. However, its role in diabetic cardiomyopathy is unknown.

To investigate the role of angiotensin-(1-9), we first induced lipotoxic stress in the heart by high-fat diet (HFD) feeding in mice. Angiotensin-(1-9) was then administered for 4 weeks using osmotic mini-pumps. Cardiac function was assessed, and insulin sensitivity was evaluated in heart tissues after insulin bolus injection. Moreover, lipotoxic stress in vitro was modelled by high glucose medium plus palmitate in neonatal rat ventricular myocytes (NRVMs).

Angiotensin-(1-9) improves myocardial function and reverts pathological cardiac remodelling under HFD feeding in mice. Moreover, angiotensin-(1-9) enhances whole-body glucose tolerance and reduces homeostatic model assessment of insulin resistance (HOMA-IR). We demonstrate that angiotensin-(1-9) increases insulin sensitivity in the heart and skeletal muscle but not in adipose tissue or the liver. Mechanistically, angiotensin-(1-9) does not affect insulin signalling in cardiomyocytes at baseline, whereas it significantly improves insulin action under lipotoxic stress through AT₂ receptors and protein kinase A.

These findings demonstrate that angiotensin-(1-9) improves cardiac function under metabolic challenge and promotes insulin signalling in cardiomyocytes under lipotoxicity, which may shed light on the therapeutic exploration against diabetic cardiomyopathy.