23-LB: Overexpression of microRNA-16 Derepresses the Mitochondrial Function to Exacerbate Cardiomyopathy in Streptozotocin-Induced Diabetic Mice

Introduction: Diabetic cardiomyopathy is initially characterized by myocardial fibrosis, dysfunctional remodeling, and associated diastolic dysfunction, later by systolic dysfunction, and eventually by clinical heart failure. MicroRNAs (miRNAs), the endogenous small non-coding RNAs, were recognized to play significant roles in diabetes. But, it remains unknown whether mitochondrial function is modulated by miRNAs during diabetic cardiomyopathy. Aim: This study investigates the potential role of microRNA-16 (miR-16) in modulating mitochondrial function during diabetic cardiomyopathy. Methods and Results: To assess the function of miR-16 in vivo, miR-16 was expressed using a adeno-associated virus serotype 9 (AAV9) viral vector in male 1-week-old mice C57BL/6J mice. At 6-week-old, these mice received three consecutive daily i.p. injections of STZ (55 mg/kg body weight) combined with 18 weeks of high-fat diet to induce T2DM. We demonstrated that miR-16 expression was slight increased in diabetic mice. Overexpression of miR-16 exacerbated diabetic cardiomyopathy which reflected by increasing myocardial fibrosis and displaying a diastolic dysfunction in STZ-induced mice. Impaired mitochondrial function was observed in electron microscopy of myocardium in mice with overexpression of miR-16. In vitro, high glucose (HG) treated cultured cardiomyocytes with overexpression miR-16 showed a worse mitochondrial damage, and inhibition of miR-16 induced a protective effects role in HG-treated cardiomyocytes. Molecular mechanisms linked to the underlying pathophysiological changes include abnormalities in AMP-activated protein kinase, p38 MAPK and PGC1α. Conclusions: In conclusion, our results show that miR-16 plays an important role in the development of diabetic cardiomyopathy in T2DM mice, which can be targeted for therapeutic intervention. Disclosure J. Zhou: None. Y. Zhu: None. J. Fan: None.