Shao Mingjing, Chen Guangdong, Lv Fengli, Liu Yanyan, Tian Hongjun, Tao Ran, Jiang Ronghuan, Zhang Wei, Zhuo Chuanjun
National Integrated Traditional and Western Medicine Center for Cardivascular Disease, China-Japan Friendship Hospital, Beijing, China.
Department of Psychological Medicine, Wenzhou Seventh People's Hospital, Wenzhou, China.
Oncotarget. 2017 Jul 18;8(29):47565-47573. doi: 10.18632/oncotarget.17735.
In the previous study, we established a mouse model of cardiac hypertrophy using transverse aortic constriction (TAC) and found that the expression of long non-coding RNAs TINCR was downregulated in myocardial tissue. The present study was designed to determine the potential role of TINCR in the pathogenesis of cardiac hypertrophy. Our results showed that enforced expression of TINCR could attenuate cardiac hypertrophy in TAC mice. Angiotensin II (Ang-II) was found to be associated with reduced TINCR expression and increased hypertrophy in cultured neonatal cardiomyocytes. RNA-binding protein immunoprecipitation assay confirmed that TINCR could directly bind with EZH2 in cardiomyocytes. The results of chromatin immunoprecipitation assay revealed that EZH2 could directly bind to CaMKII promoter region and mediate H3K27me3 modification. Knockdown of TINCR was found to reduce EZH2 occupancy and H3K27me3 binding in the promoter of CaMKII in cardiomyocytes. In addition, enforced expression of TINCR was found to decrease CaMKII expression and attenuate Ang-II-induced cardiomyocyte hypertrophy. Furthermore, our results also showed that Ang-II could increase CaMKII expression in cardiomyocytes, which consequently contributed to cellular hypertrophy. In conclusion, our findings demonstrated that TINCR could attenuate myocardial hypertrophy by epigenetically silencing of CaMKII, which may provide a novel therapeutic strategy for cardiac hypertrophy.
在先前的研究中，我们使用主动脉缩窄（TAC）建立了心脏肥大的小鼠模型，并发现长链非编码RNA TINCR在心肌组织中的表达下调。本研究旨在确定TINCR在心脏肥大发病机制中的潜在作用。我们的结果表明，TINCR的过表达可减轻TAC小鼠的心脏肥大。发现血管紧张素II（Ang-II）与培养的新生心肌细胞中TINCR表达降低和肥大增加有关。RNA结合蛋白免疫沉淀试验证实TINCR可在心肌细胞中直接与EZH2结合。染色质免疫沉淀试验结果显示EZH2可直接结合到CaMKII启动子区域并介导H3K27me3修饰。发现敲低TINCR可降低心肌细胞中CaMKII启动子的EZH2占有率和H3K27me3结合。此外，发现TINCR的过表达可降低CaMKII表达并减轻Ang-II诱导的心肌细胞肥大。此外，我们的结果还表明Ang-II可增加心肌细胞中CaMKII的表达，从而导致细胞肥大。总之，我们的研究结果表明TINCR可通过对CaMKII进行表观遗传沉默来减轻心肌肥大，这可能为心脏肥大提供一种新的治疗策略。
