Abstract
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.
Highlights
IntroductionEGCG prevents heart failure by up-regulating SERCA2a
Our data indicate that increased HDAC1 activity and binding to the promoter of the gene encoding SERCA2a (Atp2a2), which might result in the hypoacetylation of histone 3 lysine 9, in addition to chromatin regulation, result in decreased transcription factor binding to this promoter region
Further investigation showed that EGCG could inhibit the activity and binding of HDAC1 to the Atp2a2 proximal promoter region to rescue the low expression of SERCA2a and improve cardiac function
Summary
EGCG prevents heart failure by up-regulating SERCA2a This remains an increasing global disease, with an estimated prevalence of > 37.7 million individuals globally [1]. The expression levels of SERCA2a mRNA and protein were shown to be significantly decreased in animal models of pressure overload-induced heart failure [4,5,6]. Studies have shown that SERCA2a overexpression in myocytes via adenoviral gene transfer results in increased contractility and faster relaxation of the transient calcium [13, 14]; it can improve myocardial systolic and diastolic function in animals with pressure overload-induced heart failure [15,16,17]. Histone epigenetic modification was revealed to regulate SERCA2a in a mouse model of pressure overload-induced heart failure [18], indicating that the epigenetic regulation of SERCA2a might represent a new mechanism to prevent heart failure
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