PRMT5 Prevents Cardiomyocyte Hypertrophy via Symmetric Dimethylating HoxA9 and Repressing HoxA9 Expression.
PRMT5 Prevents Cardiomyocyte Hypertrophy via Symmetric Dimethylating HoxA9 and Repressing HoxA9 Expression.
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PRMT5 通过对称二甲基化 HoxA9 和抑制 HoxA9 表达来防止心肌细胞肥大
DOI：
10.3389/fphar.2020.600627
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发表时间：
2020
影响因子：
5.6
通讯作者：
Liu P
中科院分区：
文献类型：
--
作者：
Cai S;Liu R;Wang P;Li J;Xie T;Wang M;Cao Y;Li Z;Liu P
本研究揭示了蛋白精氨酸甲基转移酶5 （PRMT5）和Homebox A9 （HoxA9）在心肌细胞肥厚调节中的联系。β-肾上腺素受体激动剂异丙肾上腺素（ISO）诱导心肌细胞肥大时，PRMT5表达降低，HoxA9表达上调。沉默PRMT5或其药理抑制剂EPZ抑制PRMT5可增强心肌细胞肥厚基因脑钠肽（BNP）和β-肌球蛋白重链（β-MHC）的表达，而过表达PRMT5可抑制iso诱导的心肌细胞肥厚，提示PRMT5可改善心肌细胞肥厚。相反，HoxA9促进心肌细胞肥大，正如功能获得和功能丧失实验所暗示的那样。HoxA9参与了PRMT5对心肌细胞肥厚的调控，因为HoxA9的敲低阻止了si- rpmt5诱导的心肌细胞肥厚，HoxA9的表达削弱了PRMT5的抗肥厚作用。共免疫沉淀实验显示PRMT5和HoxA9之间存在物理相互作用。ISO或EPZ处理降低了HoxA9的对称二甲基化水平，表明HoxA9被PRMT5甲基化。此外，PRMT5抑制HoxA9的表达。染色质免疫沉淀（ChIP）实验表明，HoxA9可以与BNP启动子结合，并且这种结合亲和力被ISO或EPZ进一步增强。综上所述，本研究提示PRMT5对称二甲基化HoxA9并抑制HoxA9的表达，从而损害其与BNP启动子的结合，最终保护心肌细胞肥厚。这些发现为PRMT5心脏保护作用的机制提供了新的见解，并提出了激活PRMT5或抑制HoxA9治疗心脏肥厚的潜在治疗策略。
The present study reveals a link between protein arginine methyltransferase 5 (PRMT5) and Homebox A9 (HoxA9) in the regulation of cardiomyocyte hypertrophy. In cardiomyocyte hypertrophy induced by β-adrenergic receptor agonist isoprenaline (ISO), PRMT5 expression was decreased while HoxA9 was upregulated. Silencing of PRMT5 or inhibition of PRMT5 by its pharmacological inhibitor EPZ augmented the expressions of cardiomyocyte hypertrophic genes brain natriuretic peptide (BNP) and β-Myosin Heavy Chain (β-MHC), whereas overexpression of PRMT5 inhibited ISO-induced cardiomyocyte hypertrophy, suggesting that PRMT5 ameliorates cardiomyocyte hypertrophy. On the contrary, HoxA9 promoted cardiomyocyte hypertrophy, as implied by the gain-of-function and loss-of-function experiments. HoxA9 was involved in the regulation of PRMT5 in cardiomyocyte hypertrophy, since HoxA9 knockdown prevented si-RPMT5-induced cardiomyocyte hypertrophy, and HoxA9 expression impaired the anti-hypertrophic effect of PRMT5. Co-immunoprecipitation experiments revealed that there were physical interactions between PRMT5 and HoxA9. The symmetric dimethylation level of HoxA9 was decreased by ISO or EPZ treatment, suggesting that HoxA9 is methylated by PRMT5. Additionally, PRMT5 repressed the expression of HoxA9. Chromatin immunoprecipitation (ChIP) assay demonstrated that HoxA9 could bind to the promoter of BNP, and that this binding affinity was further enhanced by ISO or EPZ. In conclusion, this study suggests that PRMT5 symmetric dimethylates HoxA9 and represses HoxA9 expression, thus impairing its binding to BNP promoter and ultimately protecting against cardiomyocyte hypertrophy. These findings provide a novel insight of the mechanism underlying the cardiac protective effect of PRMT5, and suggest potential therapeutic strategies of PRMT5 activation or HoxA9 inhibition in treatment of cardiac hypertrophy.
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DOI：
10.1038/nrm3495
发表时间：
2013-01
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
14.9
作者：
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Feil R
DOI：
10.1038/jid.2015.400
发表时间：
2016-01
期刊：
The Journal of investigative dermatology
影响因子：
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作者：
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通讯作者：
Eckert RL
影响因子：
3.2
作者：
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通讯作者：
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影响因子：
3.5
作者：
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