心肌肥大引起Ito电流降低，是导致室性心律失常发生的重要原因。Ito下调与该通道beta亚基KChIP2表达降低密切相关，其机制尚待查明。我们前期工作首次发现，抑制组蛋白去乙酰化酶(HDAC)能上调肥大心肌细胞KChIP2表达和Ito电流。我们拟通过RNAi和基因敲除手段从细胞和整体水平进一步查明起作用的特异性HDAC靶点(类型)。还将应用离体和在体基因表达调控、染色质免疫沉淀（ChIP）等技术，从分子、细胞和整体水平阐明心肌肥大时抑制HDAC作用的以下可能机制: (1)降低H3K4去甲基化酶表达，及解除KChIP2基因启动子区HDAC对H3K4去甲基化酶的募集作用，增加该启动子区H3K4me3聚集，使KChIP2表达增加；(2)解除HDAC和Brg1抑制复合物与NF-kB结合，使该复合物对KChIP2表达的抑制作用解除，增加KChIP2表达。为心肌肥大时心律失常的治疗提供新靶点和思路。

The transient outward K+ current (Ito) is downregulated and contributes to the pathogenesis of ventricular arrhythmia in cardiac hypertrophy by prolonging action potential duration (APD) and increasing transmural dispersion of ventricular repolarization. It is well established that the downregulation of Ito is largely attributed to the reduction of KChIP2, the beta subunit of Ito. However, the mechanism underlying the decreased KChIP2 expression in hypertrophy remains largely unknown. Our pioneering work demonstrated that VPA, the pan-inhibitor for class I and class II histone deacetylase (HDAC), could up-regulate KChIP2 expression and Ito current densities in cardiac hypertrophy. In this project, we will identify the specific type of HDAC responsible for the therapeutic effect of inhibition of HDAC on KChIP2 expression and Ito in cardiac hypertrophy. Furthermore, we will investigate the underlying mechanisms. Here, we proposed two hypotheses based on our preliminary data. First, the expression of H3K4 demethalase was decreased by inhibition of HDAC, leading to increase in H3K4 methylation. Furthermore, the recruitment of H3K4 demethalase to the promoter of Kcnip2 (the gene encoding KChIP2) was decreased, resulting in attenuated enrichment of H3K4me3 at Kcnip2 promoter, resulting in down-regulation of Kcnip2 expression. Second, inhibition of HDAC dissociated the interaction of HDAC and Brg1 inhibitory complex with NF-kB at Kcnip2 promoter and prohibited the negative regulation of HDAC and Brg1 complex on Kcnip2 expression. In this project, we aim to elucidate novel epigenetic regulatory mechanisms for the downregulation of KChIP2 expression and Ito and try to find out new therapeutic strategies for the treatment of arrhythmia in hypertrophy.