Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan; Division of Translational Research, Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan; Shizuoka General Hospital, Shizuoka, Japan.
Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
J Nutr Biochem. 2022 Aug;106:109031. doi: 10.1016/j.jnutbio.2022.109031. Epub 2022 Apr 30.
While the cardioprotective functions of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and omega-3 unsaturated fatty acids have been previously demonstrated, little is known about their effects on cardiomyocyte hypertrophy. In this study, we compared the effects of EPA and DHA on hypertrophic responses in cardiomyocytes and development of heart failure in rats with myocardial infarction (MI). Both EPA and DHA significantly suppressed phenylephrine- and p300-induced cardiomyocyte hypertrophy, transcription of hypertrophy response genes, and acetylation of histone H3K9 in cardiomyocytes. EPA and DHA directly inhibited p300-histone acetyltransferase activity (IC50: 37.8 and 30.6 μM, respectively). Further, EPA- and DHA-induced allosteric inhibition of histones and competitive inhibition of acetyl-CoA, and significantly prevented p300-induced hypertrophic responses. Rats with moderate MI (left ventricular fractional shortening [FS] <40%) were randomly assigned to three groups, namely, vehicle (saline), EPA (1 g/kg), and DHA (1 g/kg). One week after the operation, rats were orally administrated with test agents for 6 weeks. Echocardiographic analysis demonstrated that both EPA and DHA treatments preserved FS and prevented MI-induced left ventricular remodeling. Furthermore, EPA and DHA significantly suppressed the MI-induced increase in myocardial cell diameter, perivascular fibrosis, mRNA levels of hypertrophic markers, fibrosis, and acetylation of histone H3K9. The effects on hypertrophic responses and the development of heart failure were not different between EPA and DHA groups. Both EPA and DHA suppressed hypertrophic responses and the development of heart failure to the same extent through the inhibition of p300-HAT activity.
二十碳五烯酸（EPA）、二十二碳六烯酸（DHA）和 ω-3 不饱和脂肪酸的心脏保护功能先前已得到证实，但它们对心肌细胞肥大的影响知之甚少。在这项研究中，我们比较了 EPA 和 DHA 对心肌梗死（MI）大鼠心肌细胞肥大反应和心力衰竭发展的影响。EPA 和 DHA 均显著抑制了去甲肾上腺素和 p300 诱导的心肌细胞肥大、肥大反应基因的转录以及心肌细胞组蛋白 H3K9 的乙酰化。EPA 和 DHA 直接抑制了 p300-组蛋白乙酰转移酶活性（IC50：分别为 37.8 和 30.6 μM）。此外，EPA 和 DHA 诱导了组蛋白的变构抑制和乙酰辅酶 A 的竞争性抑制，并显著预防了 p300 诱导的肥大反应。中度 MI（左心室缩短分数 [FS] <40%）大鼠被随机分为三组，即载体（生理盐水）、EPA（1 g/kg）和 DHA（1 g/kg）。手术后一周，大鼠开始口服试验药物 6 周。超声心动图分析表明，EPA 和 DHA 治疗均保存了 FS，防止了 MI 引起的左心室重构。此外，EPA 和 DHA 显著抑制了 MI 引起的心肌细胞直径增加、血管周围纤维化、肥大标志物、纤维化和组蛋白 H3K9 乙酰化的 mRNA 水平增加。EPA 和 DHA 组之间在肥大反应和心力衰竭发展方面的作用没有差异。EPA 和 DHA 通过抑制 p300-HAT 活性，对肥大反应和心力衰竭的发展均产生了相同程度的抑制作用。
