Novel angiotensin receptor target as therapy for the diabetic heart: the AT₂R

Diabetic-related heart complications, exemplified by heart failure, represents a growing global health burden, characterised by deterioration of cardiac function, disturbances in cardiac structure such as left ventricular geometry and tissue composition. The underlying molecular mechanisms of diabetic heart failure are multifaceted, and both inflammation and oxidative stress are identified as key drivers in disease progression. Current treatments primarily focus on glycaemic control to prevent heart failure in diabetic patients, but their direct effects on the myocardium are not always clear. Upregulation of the renin-angiotensin system in the diabetic heart presents itself as a compelling therapeutic opportunity, particularly through the counter-regulatory angiotensin II type 2 receptor (AT₂R) axis. AT₂R activation confers cardioprotection in experimental diabetes and heart failure by attenuating pathological cardiac remodelling, including fibrosis and hypertrophy. These effects are facilitated by reductions in oxidative stress and endothelial dysfunction, enhanced nitric oxide signalling and suppression of NF-κB signalling and subsequent inflammation. This review describes the progress made to date, profiling the preclinical benefits of AT₂R activation, using a suite of current and new-generation AT₂R agonists in the heart, and provides evidence for the potential therapeutic use of AT₂R agonists as a novel anti-fibrotic strategy, alone or in combination with standard therapy, for diabetic heart failure.