组蛋白甲基转移酶SET1调控血管内皮/白细胞转录机制及其在动脉粥样硬化中的意义

血管内皮细胞与白细胞在病理状态下的交互作用促进心血管系统炎症，是动脉粥样硬化发生的重要病理生理学基础。近年来的研究表明，表观遗传机器是联系促动脉粥样损伤信号与血管炎症的重要桥梁，但其中的机制尚不完全明确。组蛋白H3K4甲基转移酶SET1在哺乳动物胚胎发育中发挥必不可少的作用，但对SET1调控胚胎发育完成后的病理生理过程尚无系统研究。我们前期研究发现，SET1在巨噬细胞中介导LPS诱导的促炎介质基因转录并且在内皮细胞中介导Ang II诱导的内皮素基因转录。SET1在罹患动脉粥样硬化小鼠血管中表达上调并通过激活细胞黏附分子转录介导内皮细胞与白细胞的互相作用。因此，我们提出假说，即SET1通过调控内皮细胞/白细胞表达谱，进而促进内皮细胞与白细胞在病理状态下的交互作用，最终导致动脉粥样斑块的形成。我们希望通过这一研究，揭示动脉粥样损伤过程中的共有表观遗传机制，为临床干预动脉粥样硬化提供新的靶点。

The interplay between vascular endothelial cells and leukocytes promotes vascular inflammation and constitutes a key pathophysiological basis underlying atherogenesis. Recent investigations have unequivocally established a connection between pro-atherogenic signals and vascular inflammation bridged by the epigenetic machinery. The underlying mechanism, however, is not completely understood. SET1 is a conserved histone H3K4 methyltransferase in eukaryotes and plays an essential in mammalian embryogenesis. Its role in the regulation of post-embryonic pathophysiological processes is not entirely clear. Our preliminary data suggest that SET1 mediates LPS-induced transactivation of pro-inflammatory genes in macrophages and Ang II-induced transactivation of endothelin in endothelial cells. In addition, we have also found that SET1 expression is unregulated in the vessels of mice fed on a high-fat diet to develop atherosclerosis compared to the control mice. SET1 mediates the adhesion of leukocytes to endothelial cells in vitro by stimulating the transcription of adhesion molecules. Based on these findings, we propose that under the influence of pro-atherogenic signals, SET1 alters the interplay between vascular endothelial cells and leukocytes by modulating their transcriptomes, which consequently leads to the development of atherosclerotic plaques. Our aim is to unveil a novel epigenetic mechanism underlying the formation of atherosclerotic lesions with the hope that it will provide novel target for the intervention of atherosclerosis.