Abstract 16402: Epa and Dha Suppressed Myocardial Infarction-induced Systolic Dysfunction by Inhibiting P300 Hat Activity

Abstract

Introduction: p300, an intrinsic histone acetyltransferase (HAT), has a crucial role in the pathological cardiac hypertrophy and the development of heart failure in vivo . Although many studies have shown a cardioprotective effect of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), omega-3 fatty acids, little is known about the effects of these acids on cardiac hypertrophy. Aim: This study investigated whether EPA and DHA inhibited the development of heart failure in rats with myocardial infarction (MI). Methods and Results: To investigate the effects on cardiomyocyte hypertrophy in cultured cardiomyocytes, neonatal rat cultured cardiomyocytes were stimulated with phenylephrine (PE). EPA or DHA significantly inhibited PE-induced cardiomyocyte hypertrophy. EPA and DHA repressed to the same extent PE-induced acetylation of histone H3 in cultured cardiomyocytes. An in vitro HAT assay was performed to determine the direct inhibition of p300-HAT activity. The results revealed that EPA and DHA significantly inhibited p300-HAT activity. To assess whether EPA and DHA suppress p300-HAT activity directly in cultured cardiomyocytes, p300 was overexpressed in cultured cardiomyocytes. Treatment with EPA or DHA inhibited the overexpression of p300-induced cardiomyocyte hypertrophy in cultured cardiomyocytes. MI-operated rats (FS < 40%) were randomly assigned to 3 groups: vehicle, EPA (1 g/kg) and DHA (1 g/kg). One week after MI operation, oral administrations were repeated for 6 weeks. Echocardiographic analysis demonstrated that EPA and DHA significantly improved MI-induced cardiac dysfunction. In addition, Masson's trichrome staining showed that EPA and DHA inhibit MI-induced fibrosis response in MI rats. EPA and DHA repressed MI-induced hypertrophic response gene transcriptions such as ANF and BNP with RT-PCR. Western blotting demonstrated that inhibited MI-induced H3K9 acetylation in rats . Conclusion: EPA and DHA suppressed hypertrophic responses to the same extent, through the direct inhibition of p300-HAT activity and repressed MI-induced development of heart failure.