Epigenetic Mechanisms Of EGCG Up-regulating Age-related SERCA2a Low-expression In Mice

ObjectiveDiastolic dysfunction is common cardiovascular disease in the elderly,and associated with SERCA2 a low-expression.Histone acetylation of ATP2a2 promoter regions may be one of the key mechanisms of SERCA2 a expression.Studies have found that EGCG can significantly increase levels of histone acetylation and influence gene transcription and expression.Therefore,in this research,after treated with EGCG,it is to explore whether(-)-epigallo-catechin-3-gallate could increase SERCA2 a expression and influence cardiac histological morphology.MethodsSixteen-month-old C57 BL/6 male aging mice were randomly divided into EGCG group,DMSO group and untreated old group,and three-month-old male mice were used as young group.EGCG group and DMSO group were treated with EGCG and DMSO by intraperitoneal injection for 8 weeks,respectively.The heart tissues of each group were collected for the following analysis.RT-PCR was used to measure the m RNA-expression of Atp2a2 and HDAC1.Meanwhile,the expression of SERCA2 a was detected by Western blot.The binding levels of histone deacetylase 1(HDAC1),acetylated lysine 4 on histone H3(Ac H3K4),acetylated lysine 9 on histone H3(Ac H3K9),acetylated lysine 27 on histone H3(Ac H3K27)and transcription factors GATA4 and Mef2 c near the proximal promoter region of Atp2a2 gene were determined by Ch IP-Q-PCR.Myocardial ultrastructural changes were performed by transmission electron microscope.Cardiac fibrosis was detected by masson staining and myocardial apoptosis was detected by Tunel assay.Results1.Compared with old and DMSO groups,SERCA2 a m RNA and protein levels were both increased in EGCG and young groups,(p<0.05).2.Expression of HDAC1 m RNA and binding levels near promotor of ATP2a2 of EGCG and young groups were significantly lower than that of old and DMSO groups(p<0.05).3.Both Ac H3 and Ac H3K9 levels near promotor of ATP2a2 of EGCG and groups were improved,in contrary to old and DMSO groups(p<0.05).There were no significant differences in Ac H3K4 levels near promotor of ATP2a2 among all groups(p>0.05).Although Ac H3K27 level near promotor of ATP2a2 was significant higher than three other groups(p<0.05),there no significant differences among the three groups(p>0.05).4.Binding levels of GATA4 and Mef2 c near promotor of ATP2a2 were increased after EGCG treatment(p<0.05).5.Compared with old group,sarcomere dissolution,cardiac fibrosis and myocardial apoptosis of EGCG group were decreased in aging mice.Conclusion 1.Hypoacetylation of Ac H3K9 mediated by HDAC1 may play a critical role in low-expression of SERCA2 a in aging hearts,and EGCG could inhibit the process to increase the expression of SERCA2 a in aging mice.2.EGCG might retard myofilament destruction,cardiac fibrosis and myocardial apoptosis in aging mice.