HDAC6基于Cavelin-1乙酰化修饰介导巨噬细胞泡沫化调控动脉粥样硬化的作用及机制研究

异常脂质代谢导致的巨噬细胞泡沫化在动脉粥样硬化（Atherosclerosis，AS）中起关键作用，但其确切的上游分子机制还不清楚，近年研究表明表观遗传修饰在AS发生中具有重要作用。我们发现组蛋白去乙酰化酶-6（HDAC6）蛋白在临床早期AS斑块中表达显著降低。在AS模型ApoE-/-小鼠中敲除HDAC6，明显促进AS的发展。在巨噬细胞中HDAC6基因沉默导致显著的脂滴沉积，形成泡沫细胞。因此我们提出HDAC6是巨噬细胞泡沫化的重要分子基础，其表达下降，引起脂质代谢异常，介导泡沫细胞形成，从而促进AS的发生发展。我们拟通过高通量的乙酰化组学、Microarray、代谢组学来研究巨噬细胞泡沫化中蛋白乙酰化、信号通路变化及代谢特征及调控网络图谱。在此基础上筛选出HDAC6介导泡沫细胞形成和AS发生的关键作用底物及主要作用机制，为治疗AS探索新的表观遗传干预靶点提供理论基础。

The macrophage-derived foam cells play a crucial role in atherosclerosis. It is widely believed that the aberrant lipid metabolism leads to foam cell formation,but the exact upstream molecular mechanism keeps elusive. In this study, we found a novel function of histone deacetylase-6 (HDAC6) in negatively regulating macrophages-derived foam cell formation, which potentially played a protective role in atherosclerosis. We found that HDAC6 protein levels in atherosclerosis plaque of atherosclerosis patients were markedly decreased, compared to artery endothelial tissue in healthy. In ApoE-/-mice atherosclerosis model, HDAC6 deficiency promoted the development of AS. In macrophage cell line RAW264.7 and primary macrophages, HDAC6 deficiency lead to significant foam cell formation upon ox-LDL incubation. In HDAC6 KO mice, high-fat diet induced lipid accumulation in liver, increasing liver size, compared to WT mice. In contrast overexpression of HDAC6 markedly inhibited foam cell formation, but HDAC6 catalytic deficiency mutant (HDAC6 CD) failed, indicating the deacetylation activity of HDAC6 was required for regulating foam cell formation. In addition, we find that HDAC6 protein levels in atherosclerosis plaque of atherosclerosis patients were markedly decreased, compared to artery endothelial tissue in healthy. Thus we propose that HDAC6 is the important molecular basis of foam cell formation. The decrease in HDAC6 expression increases the acetylation level of lipid mechanism related targets, leading to foam cell formation and the atherosclerosis development. We plan to perform high-through acetylome, microarray, and metabonomics analysis to screen out the direct target of HDAC6 and main signal pathways involved in foam cell formation. Nex we investigate HDAC6’s role in atherosclerosis in ApoE-/-mice by conditional HDAC6 deficiency in immune cells, for providing a potential intervention target in atherosclerosis.