O-GlcNAcylation-mediated endothelial metabolic memory contributes to cardiac damage via small extracellular vesicles.

Diabetic individuals with well-controlled blood glucose still have an increased risk of heart failure. This process may be mediated by metabolic memory, a phenomenon showing that hyperglycemia has long-term negative effects even after normoglycemia. Here, we found that despite later normoglycemia with insulin, long-term diabetes-derived plasma small extracellular vesicle (sEV) miR-15-16 exhibited sustained deleterious effects on cardiomyocytes and induced cardiac dysfunction in healthy animals, displaying a memory feature. Artery endothelial cells were the primary origin of sEV miR-15-16. Mechanistically, the continuous sEV miR-15-16 release is due to the sustained activation of CaMK2a following the high glucose-elicited positive feedback loop of CaMK2a/O-GlcNAcylation in endothelial cells. In patients with diabetes, elevated sEV miR-15-16 was significantly associated with cardiac dysfunction, regardless of blood glucose or HbA1c. Together, our findings demonstrate that diabetes-induced O-GlcNAcylation and activation of CaMK2a mediate endothelial metabolic memory, which induces continuous release of sEV miR-15-16 and subsequent cardiac damage.