Identify the molecular basis linking diabetes with MI/R injury is scientifically important and may provide effective therapeutic approaches. Recent studies indicated that enhanced Dynamin-related protein 1 (Drp1)-mediated mitochondrial fission is involved in both diabetic hearts and ischemic hearts. We hypothesized that inhibition of Drp1-mediated mitochondrial fission may be effective to reduce MI/R injury in diabetic hearts. High-fat diet and streptozotocin-induced diabetic mice were subjected to MI/R or sham operation. Mdivi-1 (1.2 mg/kg), a small molecule inhibitor of Drp1 or vehicle was administrated 15 min before the onset of reperfusion. Outcome measures included mitochondrial morphology, mitochondrial function, myocardial injury, cardiac function and oxidative stress. Mitochondrial fission was significantly increased following MI/R as evidenced by enhanced translocation of Drp1 to mitochondria and decreased mitochondrial size. Delivery of Mdivi-1 into diabetic mice markedly inhibited Drp1 translocation to the mitochondria and reduced mitochondrial fission following MI/R. Inhibition of Drp1-mediated mitochondrial fission increased mitochondrial complex I/II/III/IV activities and ATP content and improved cardiac function following MI/R (n = 8, P < 0.01). Moreover, inhibition of Drp1 reduced myocardial infarct size (28.7 ± 4.2% vs. 45.3 ± 4.7% n = 8, P < 0.01) and serum cardiac troponin and lactate dehydrogenase activities. These cardioprotective effects were associated with decreased cardiomyocyte apoptosis and malondialdehyde production and increased activities of antioxidant enzyme manganese superoxide dismutase (n = 8, P < 0.01). These data suggest that Drp1-mediated mitochondrial fission may be a potential novel therapeutic target for diabetic cardiac complications.
M. Ding: None. J. Feng: None. Z. Li: None. F. Fu: None.