Abstract 15178: Mitochondrial Dynamic Modulators Mitigates Mitochondrial Dynamic Index, Biogenesis and Metabolic Impairments in Prediabetic Rats With Cardiac Ischemia-reperfusion Injury

Abstract

Introduction: Long-term exposure to high-fat diet (HFD) caused obesity, which not only was positively associated with cardiovascular disorders but also had a negative impact on the outcome of acute myocardial ischemia-reperfusion (I/R) injury. Uncontrolled fission and diminished fusion of cardiac mitochondria augment the impairment of mitochondrial biogenesis and metabolism which have been implicated in metabolic diseases and I/R injury pathology. Since cardioprotective efficacy of acute administration of mitochondrial fission inhibitor (Mdivi-1) and fusion promoter (M1) have previously been reported, the effects of chronic treatment with both modulators on cardiac mitochondrial dynamics, biogenesis and lipid metabolism in prediabetic rats subjected to cardiac I/R injury have never been elucidated. Hypothesis: Chronic treatment of Mdivi-1 and M1 after acute myocardial I/R improve mitochondrial dynamic index, biogenesis and metabolic pathway in prediabetic rats. Methods: Male Wistar rats (n=18) were fed with HFD. After 12 weeks, all rats were randomly divided into: 1) HFV (Vehicle, 0.1% DMSO), 2) HFMd (Mdivi-1, 1.2 mg/kg), and 3) HFM1 (M1, 2 mg/kg) with intraperitoneal injection for 14 days. Then, all rats underwent 30 minutes of left anterior descending coronary artery occlusion followed by reperfusion for 120 minutes. The expression of mitochondrial dynamics (p-Drp1 ser616 per Mfn2 ratio or dynamic index), biogenesis (PGC1- α) and lipid metabolism (CPT1) proteins from ischemic area of heart were determined. Results: Chronic treatment of Mdivi-1 and M1 similarly improved cardiac mitochondrial dynamic index (p-Drp1 ser616 per Mfn2 ratio), increased PGC1-α and CPT1 expression levels, when compared to HFV (Fig). Conclusions: Modulating mitochondrial dynamics by chronic treatment of Mdivi-1 and M1 improved cardiac mitochondrial dynamic index, biogenesis and metabolic pathway in prediabetic rats following acute myocardial I/R injury.