The polyunsaturated fatty acids, EPA and DHA, ameliorate myocardial infarction-induced heart failure by inhibiting p300-HAT activity in rats
The polyunsaturated fatty acids, EPA and DHA, ameliorate myocardial infarction-induced heart failure by inhibiting p300-HAT activity in rats
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DOI：
10.1016/j.jnutbio.2022.109031
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发表时间：
2022-05-25
影响因子：
5.6
通讯作者：
Morimoto, Tatsuya
中科院分区：
文献类型：
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作者：
Sunagawa, Yoichi;Katayama, Ayumi;Morimoto, Tatsuya
虽然二十碳五烯酸 (EPA)、二十二碳六烯酸 (DHA) 和 omega-3 不饱和脂肪酸的心脏保护功能已被证实，但人们对其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 对心肌梗塞 (MI) 大鼠心肌细胞肥大反应和心力衰竭发展的影响。 EPA 和 DHA 均显着抑制去氧肾上腺素和 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中组蛋白 H3K9 的乙酰化。 EPA和DHA直接抑制p300-组蛋白乙酰转移酶活性（IC50：分别为37.8和30.6μM）。此外，EPA 和 DHA 诱导的组蛋白变构抑制和乙酰辅酶 A 的竞争性抑制，并显着阻止 p300 诱导的肥大反应。中度 MI（左心室缩短分数 [FS] < 40%）的大鼠被随机分为三组，即载体（盐水）、EPA（1 g/kg）和 DHA（1 g/kg）。术后1周，给大鼠口服受试药物，持续6周。超声心动图分析表明，EPA 和 DHA 治疗均能保留 FS 并防止 MI 引起的左心室重构。此外，EPA 和 DHA 显着抑制 MI 诱导的心肌细胞直径增加、血管周围纤维化、肥大标志物 mRNA 水平、纤维化和组蛋白 H3K9 乙酰化。 EPA 组和 DHA 组对肥厚反应和心力衰竭发展的影响没有差异。 EPA 和 DHA 均通过抑制 p300-HAT 活性，在相同程度上抑制肥厚反应和心力衰竭的发展。 (C) 2022 Elsevier Inc. 保留所有权利。
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 mu M, 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. (C) 2022 Elsevier Inc. All rights reserved.