Inhibition of Cardiomyocyte Hypertrophy by Protein Arginine Methyltransferase 5
Inhibition of Cardiomyocyte Hypertrophy by Protein Arginine Methyltransferase 5
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蛋白精氨酸甲基转移酶5抑制心肌细胞肥大
DOI：
10.1074/jbc.m114.577494
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发表时间：
2014-08-29
影响因子：
4.8
通讯作者：
Sun, Jianxin
中科院分区：
文献类型：
--
作者：
Chen, Ming;Yi, Bing;Sun, Jianxin
背景：蛋白精氨酸甲基转移酶5 （PRMT5）是一种II型蛋白精氨酸甲基转移酶，可催化靶蛋白内精氨酸残基的对称二甲基化。结果：PRMT5与心肌细胞中的GATA4相互作用并甲基化。结论：PRMT5通过降低GATA4转录活性抑制心肌细胞的肥厚反应。意义：靶向PRMT5可能是预防心脏肥厚和心力衰竭的一种新的治疗策略。蛋白精氨酸甲基转移酶5 （PRMT5）是一种催化靶蛋白内精氨酸残基对称二甲基化的蛋白精氨酸甲基转移酶，涉及从基因表达调控到细胞增殖和分化的许多重要细胞过程。PRMT5在心脏高度表达；然而，PRMT5在心脏中的功能作用在很大程度上仍然难以捉摸。在本研究中，我们发现PRMT5通过共免疫沉淀在共转染HEK293T细胞和新生大鼠心肌细胞中特异性地与GATA4相互作用。重要的是，这种相互作用导致GATA4在229、265和317位点的精氨酸甲基化，从而抑制GATA4的转录活性，主要是通过阻断心肌细胞中p300介导的GATA4乙酰化。此外，在苯肾上腺素刺激的心肌细胞中，PRMT5的过表达显著抑制了GATA4的乙酰化和心脏肥厚反应，而PRMT5的下调则诱导了GATA4的激活和心肌细胞肥厚。此外，在苯肾上腺素的刺激下，PRMT5易位到细胞质中，从而减轻了其对细胞核中GATA4活性的抑制，导致心肌细胞中肥厚基因的表达。这些发现表明，PRMT5是心肌肥厚信号的重要调节因子，并提示旨在激活心脏PRMT5的策略可能代表了预防心脏肥厚和心力衰竭的潜在治疗方法。
Background: Protein arginine methyltransferase 5 (PRMT5) is a type II protein arginine methyltransferase that catalyzes the symmetrical dimethylation of arginine residues within target proteins. Results: PRMT5 interacts with and methylates GATA4 in cardiomyocytes. Conclusion: PRMT5 suppresses hypertrophic responses in cardiomyocytes by attenuating GATA4 transcriptional activity. Significance: Targeting PRMT5 may represent a novel therapeutic strategy for preventing cardiac hypertrophy and heart failure.Protein arginine methyltransferase 5 (PRMT5), a protein arginine methyltransferase that catalyzes the symmetrical dimethylation of arginine residues within target proteins, has been implicated in many essential cellular processes ranging from the regulation of gene expression to cell proliferation and differentiation. PRMT5 is highly expressed in the heart; the functional role of PRMT5 in the heart, however, remains largely elusive. In the present study, we show that PRMT5 specifically interacts with GATA4 in both co-transfected HEK293T cells and neonatal rat cardiomyocytes by co-immunoprecipitation. Importantly, this interaction leads to the arginine methylation of GATA4 at positions of 229, 265, and 317, which leads to an inhibition of the GATA4 transcriptional activity, predominantly through blocking the p300-mediated acetylation of GATA4 in cardiomyocytes. Moreover, overexpression of PRMT5 substantially inhibited the acetylation of GATA4 and cardiac hypertrophic responses in phenylephrine-stimulated cardiomyocytes, whereas knockdown of PRMT5 induced GATA4 activation and cardiomyocyte hypertrophy. Furthermore, in response to phenylephrine stimulation, PRMT5 translocates into the cytoplasm, thus relieving its repression on GATA4 activity in the nucleus and leading to hypertrophic gene expression in cardiomyocytes. These findings indicate that PRMT5 is an essential regulator of myocardial hypertrophic signaling and suggest that strategies aimed at activating PRMT5 in the heart may represent a potential therapeutic approach for the prevention of cardiac hypertrophy and heart failure.