Diabetes Exacerbates Myocardial Ischemia/Reperfusion Injury by Down-Regulation of MicroRNA and Up-Regulation of O-GlcNAcylation

Visual Abstract
Highlights • Optimal treatment for patients with diabetes and myocardial infarction remains a challenge. • Hyperglycemia- and hyperinsulinemia-induced miR-24 reduction and O-GlcNAcylation in the diabetic heart contributes to poor survival in diabetic myocardial I/R and increased infarct size post-I/R. • Overexpression of miR-24 in murine hearts significantly reduces myocardial infarct size. • miR-24 targets multiple key proteins including O-GlcNac transferase, ATG4A (a key protein in autophagy), and BIM (a pro-apoptosis protein) to protect the myocardium from I/R injury. • miR-24 is a promising therapeutic candidate for diabetic I/R injury.
Summary Management for patients with diabetes experiencing myocardial infarction remains a challenge. Here the authors show that hyperglycemia- and hyperinsulinemia-induced microRNA-24 (miR-24) reduction and O-GlcNAcylation in the diabetic heart contribute to poor survival and increased infarct size in diabetic myocardial ischemia/reperfusion (I/R). In a mouse model of myocardial I/R, pharmacological or genetic overexpression of miR-24 in hearts significantly reduced myocardial infarct size. Experimental validation revealed that miR-24 targets multiple key proteins, including O-GlcNac transferase, ATG4A, and BIM, to coordinately protect the myocardium from I/R injury. These results establish miR-24 as a promising therapeutic candidate for diabetic I/R injury.