Abstract 410: Inhibiting Mitochondrial Fission in Progressive Atherosclerosis Protects Against Ischemia/Reperfusion Injury

Abstract

Introduction: Two opposing highly regulated mitochondrial processes, division (fission) and fusion, determine cell-type specific mitochondrial morphology, intracellular distribution and activity. Mitochondrial dysfunction has been implicated in atherogenesis and in cardiac ischemia/reperfusion (I/R) injury. Hypothesis: We hypothesize that increased mitochondrial fission plays a role in progressive atherosclerosis and protection in I/R injury. Methods and Results: Male apolipoprotein E knockout mice (ApoE-/-) were fed either a high-fat diet (21% lard & 0.15% cholesterol - HFD) or chow diet for 24 weeks from weaning. Compared to their chow fed littermates, mice fed a HFD demonstrated smaller, shorter and reduced density of left ventricular (LV) interfibrillar mitochondria suggestive of mitochondrial fission by electron microscopy. Furthermore, there was decreased expression of the mitochondrial fusion proteins, optic atrophy 1 and mitofusin 1 and increased fission protein Fis 1. Whilst the proteins Mfn2 and Drp1 were unchanged. On ischemia, LV tissue expression of fission proteins was increased in both groups. In isolated perfused hearts subjected to 30 min ischemia and 120 min reperfusion inhibition of the Drp1-mediated fission with Mdivi-1 (25 μM) at the onset of reperfusion significantly reduced infarct size (n=6/group). Inhibition of the DRP1-mediated fission at serine 637 in langendorff hearts conferred relatively more cardio-protection in the chow fed mice compared to western diet (19.93% ± 2.219%, n=5 versus 29.61% ± 2.517%, n=6; p < 0.05). The reduction in myocardial necrosis was corroborated by a significantly reduced release of creatine kinase and recovery of coronary flow. Conclusion: Inhibiting mitochondrial fission protects hearts against ischemia/reperfusion injury in progressive atherosclerosis.