Abstract 17833: Heterozygous Disruption of Drp-1 Induces Development of Basal Cardiac Dysfunction and Enhances Myocardial Injury in Response to Ischemia/Reperfusion
Mitochondrial fission and fusion are essential for maintaining mitochondrial quality control. However, their role in cardiac development and stress resistance remains unknown. Dynamin-related protein 1 (Drp-1) plays an essential role in mediating mitochondrial fission. Although mice with cardiac specific homozygous Drp-1 KO were not born, those with cardiac specific heterozygous Drp-1 KO were viable at 12 weeks, suggesting that Drp-1 is required for normal postnatal development but that one functional allele is sufficient during this period. Although cardiac function in Drp-1 hetero KO mice was normal at 12 weeks of age, left ventricular ejection fraction in Drp-1 hetero KO mice decreased with age and was significantly lower than in control mice at 24 weeks of age (60.2±3.8 vs 75.8±4.8%, p<0.01). The survival rate was significantly lower in Drp-1 hetero KO mice than in control mice (p<0.05 at 48 weeks) and all hetero KO mice died within a year. In order to evaluate the role of endogenous Drp-1 in mediating protection against stress in vivo, 12-week-old Drp-1 hetero KO and control mice were subjected to myocardial ischemia (30min)/reperfusion (24 hours). The infarct size /area at risk after I/R, as evaluated with tetrazolium chloride staining, was significantly greater in Drp-1 hetero KO mice than in control mice (55.2±3.0 vs 40.2±1.6%). There was no significant difference in the level of LC3 II or p62 between Drp-1 hetero KO and control mice at baseline at 12 weeks of age. However, there was significantly less LC-3 II (0.56±0.12 vs 1.02±0.14, P<0.05) and more p62 (1.02±0.14 vs 0.34±0.08, P<0.05) after I/R in Drp-1 hetero KO mice hearts than in control hearts. Homozygous downregulation of Drp-1 in cultured cardiomyocytes suppressed glucose deprivation-induced decreases in mitochondrial DNA content (3.07±0.26 vs 1.05±0.07, P<0.01), suggesting that downregulation of Drp-1 suppresses mitophagy in cardiomyocytes. These results suggest that inhibition of mitochondrial fission via downregulation of Drp-1 leads to development of cardiomyopathy at baseline and enhances myocardial injury in response to I/R, possibly through suppression of mitophagy.
- © 2013 by American Heart Association, Inc.