Eicosapentaenoic acid mediates mitochondrial fatty acid composition and fusion protein OPA-1 in associated with preservation of oxidative phosphorylation after myocardial infarction

Abstract

Purpose: Eicosapentaenoic acid (EPA) is a first line drug in the management after myocardial infarction. Mitochondria are major contributors to energy metabolism and recent mounting evidence suggests that mitochondrial dynamics, such as fusion and fission, has a pivotal role in regulating mitochondrial function. This study was designed to determine whether oral EPA mediates mitochondrial fatty acid composition, dynamics, and oxidative phosphorylation, leading to the attenuation of cardiac remodeling after myocardial infarction (MI). Methods and results: Anterior MI was produced in male rats by ligating the left anterior descending coronary artery (MI group). In the EPA-treated group, EPA (1,000 mg/kg/day) was administrated for 12 weeks after coronary ligation (MI+EPA group). Myocardial infarct size and blood pressure were comparable between groups. At 12 weeks after MI, mitochondria were isolated in non-infarcted myocardium and mitochondrial fatty acid composition was determined using gas chromatography mass spectrometry. In EPA+MI group, mitochondrial EPA content was approximately 10 times higher than that in untreated-MI group. Cardiac function was assessed by echocardiography and 2F micro-manometer-tipped catheter at 12 weeks of MI. EPA significantly improved %fractional shortening, +dP/dt, and -dP/dt, and reduced left ventricular (LV) end-diastolic diameter and pressure. In addition, histological examination showed EPA significantly suppressed myocyte hypertrophy and interstitial fibrosis in non-infarcted myocardium by 15% and 30%, respectively. Levels of ATP in cardiac tissue were measured by high-performance liquid chromatography and mitochondrial oxidative phosphorylation was assessed by O2 consumption using isolated mitochondria. After 12 weeks after MI, ATP contents in non-infarcted myocardium were significantly decreased, and mitochondrial complex II, III, and IV activities were also impaired, while EPA treatment significantly preserved mitochondrial complex activities, as a consequence of an increment in myocardial ATP content. Furthermore, MI decreased optic atrophy-1 (OPA-1) protein, a mitochondrial fusion protein, without any effects on dynamin-related protein-1 (Drp-1) protein, a mitochondrial fission protein, leading to attenuation of mitochondrial damage. Conclusion: These results suggest that oral EPA administration mediates mitochondrial EPA composition, preserves mitochondrial fusion protein OPA-1 and function of oxidative phosphorylation, leading to the attenuation of left ventricular remodeling after MI.