Epigallocatechin-3 gallate prevents pressure overload-induced heart failure by up-regulating SERCA2a via histone acetylation modification in mice
Epigallocatechin-3 gallate prevents pressure overload-induced heart failure by up-regulating SERCA2a via histone acetylation modification in mice
复制标题
表没食子儿茶素 3 没食子酸酯通过组蛋白乙酰化修饰上调 SERCA2a，预防压力超负荷诱发的心力衰竭
DOI：
10.1371/journal.pone.0205123
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发表时间：
2018-10-04
期刊：
影响因子：
3.7
通讯作者：
Tian, Jie
中科院分区：
文献类型：
--
作者：
Liu, Lifei;Zhao, Weian;Tian, Jie
心力衰竭是一种常见的、代价高昂的、可能致命的疾病。心肌肌浆网钙-三磷酸腺苷酶(SERCA2a)在心功能调节中起着重要作用。此前，SERCA2a在心力衰竭小鼠中的表达较低。表没食子儿茶素没食子酸酯(EGCG)可作为表观遗传调节剂发挥作用，已有报道可增强心功能。然而，潜在的表观遗传调控机制仍不清楚。在这项研究中，我们研究了EGCG是否可以通过组蛋白乙酰化上调SERCA2a，从而发挥预防心力衰竭的作用。为此，我们通过实施微创横断主动脉缩窄(TAC)手术建立了心力衰竭的小鼠模型，并用此来测试EGCG的效果。与假手术组相比，TAC+EGCG组的心功能接近正常。TAC组SERCA2a在mRNA和蛋白水平表达均降低，而TAC+EGCG组SERCA2a表达增强。在TAC组，AcH3和AcH3K9在Atp2a2(编码SERCA-2a基因)启动子区域附近降低，而在TAC+EGCG组升高。同时，在TAC组，HDAC1活性和Atp2a2启动子附近的结合增加，但加入EGCG后，HDAC1活性和结合减少。此外，在TAC心脏中，Atp2a2启动子区域附近的GATA4和MEF2C的结合水平降低，这可能是由组蛋白低乙酰化引起的；这一点被EGCG逆转。总之，通过组蛋白乙酰化修饰上调SERCA2a在EGCG介导的预防压力超负荷所致心力衰竭中发挥作用，这可能是治疗心力衰竭的一个新的药理学靶点。
Heart failure is a common, costly, and potentially fatal condition. The cardiac sarcoplasmic reticulum Ca-ATPase (SERCA2a) plays a critical role in the regulation of cardiac function. Previously, low SERCA2a expression was revealed in mice with heart failure. Epigallocatechin-3-gallate (EGCG) can function as an epigenetic regulator and has been reported to enhance cardiac function. However, the underlying epigenetic regulatory mechanism is still unclear. In this study, we investigated whether EGCG can up-regulate SERCA2a via histone acetylation and play role in preventing heart failure. For this, we generated a mouse model of heart failure by performing a minimally invasive transverse aortic constriction (TAC) operation and used this to test the effects of EGCG. The TAC+EGCG group showed nearly normal cardiac function compared to that in the SHAM group. The expression of SERCA2a was decreased at both the mRNA and protein levels in the TAC group but was enhanced in the TAC+EGCG group. Levels of AcH3 and AcH3K9 were determined to decrease near the promoter region of Atp2a2 (the gene encoding SERCA-2a) in the TAC group, but were elevated in the TAC+EGCG group. Meanwhile, HDAC1 activity and binding near the Atp2a2 promoter were increased in the TAC group but decreased with EGCG addition. Further, binding levels of GATA4 and Mef2c near the Atp2a2 promoter region were reduced in TAC hearts, which might have been caused by histone hypoacetylation; this was reversed by EGCG. Together, upregulation of SERCA2a via the modification of histone acetylation plays a role in EGCG-mediated prevention of pressure overload-induced heart failure, and this might represent a novel pharmacological target for the treatment of heart failure.