动脉粥样硬化（AS）斑块破裂的高发率、高死亡率及现有治疗的不理想敦促我们从新的角度去寻找治疗药物。PPARγ-LXR-ABCA1通路是促使脂质外排、减小斑块的重要通路。PPARγ作用广泛，我们希望找到仅作用于脂质外排直接蛋白、尽可能少影响PPARγ表达的药物。申请者在课题组多年研究蛋白质乙酰化的基础上，受PPARγ蛋白能被HDAC抑制剂乙酰化启发，尝试给予高脂喂养的ApoE-/-小鼠HDAC抑制剂TSA,发现AS斑块体积显著减小。PPARγ蛋白水平不变，但脂质外排下游蛋白LXR、ABCA1等表达增高。这提示：HDAC抑制剂可能通过乙酰化PPARγ激活巨噬细胞脂质外排通路抗动脉粥样硬化。本课题首次提出PPARγ蛋白乙酰化可作为新的抗AS的靶点，我们将进一步明确PPARγ乙酰化的位点，阐明乙酰化PPARγ在AS发生发展过程中的机制，为设计新型的HDAC抑制剂提供理论依据。

High mortality due to atherosclerotic plaque rupture poses urgent need to find novel anti-atherosclerosis drugs. PPARγ-LXR-ABCA1 pathway is critical for cholesterol efflux which decreases atherosclerotic plaque volume. We aim to search for compounds/drugs that do not affect PPARγ expression but act directly on downstream efflux protein. Inspired by the fact that PPARγ can be acetylized by histone deacetylase inhibitors, we intervened ApoE-/- with Trichostatin A (TSA), an HDAC inhibitor with a broad spectrum of epigenetic activities. Our previous data indicated that the plaque volume in ApoE-/- mice was significantly reduced by TSA. In addition, proteins playing key role in cholesterol efflux such as LXR (liver X receptor), ABCA1 and ABCG1(ATP-binding cassette transporter A1&G1) were up-regulated. It suggested that atherosclerosis can be attenuated via activation of PPARγ-LXR-ABCA1 pathway upregulated by TSA. We also found that TSA was able to induce PPARγ acetylation, suggesting that PPARγ was a direct target of protein acetylation. This project will further explore the mechanism of HDAC inhibitors as a new therapy in the treatment of atherosclerosis, and provide new insight for designing more effective anti-atherosclerosis drugs.