炎症介导的血管内皮损伤和动脉粥样硬化是心脑血管疾病的共同病理基础，巨噬细胞促炎极化是其核心机制，我们前期实验发现E2F1介导线粒体能量代谢调控在巨噬细胞促炎极化中起着关键作用。E2F1可通过抑制线粒体有氧代谢，增强糖酵解代谢水平，促进巨噬细胞向促炎表型极化；敲减E2F1分子可增强线粒体有氧代谢，减轻巨噬细胞促炎极化介导的血管内皮炎症损伤，促进血管再内皮化修复，但具体机制尚有待阐明。通过全转录组RNA测序和染色质免疫共沉淀分析推测，丙酮酸脱氢酶激酶4（PDK4）可能是介导E2F1调控巨噬细胞线粒体代谢和促炎极化的关键分子，过表达PDK4可逆转E2F1敲减对巨噬细胞功能的影响。本课题拟结合线粒体生物学、代谢组学及血管生物学等研究方法，从线粒体能量代谢角度探讨E2F1调控巨噬细胞促炎极化及血管内皮炎症损伤的新机制，为早期防治心脑血管疾病提供新的干预靶点和治疗策略。

Inflammation-mediated vascular endothelial injury and atherosclerosis is the common pathology basis of cardio-cerebrovascular diseases. The proinflammatory polarization of microphages is the core mechanism. Mitochondrial metabolism is now considered as an important regulator of macrophage proinflammatory polarization, and E2F1 is one of the key modulators of mitochondrial metabolism. Our preliminary study showed that E2F1 regulated macrophage proinflammatory polarization through suppressing mitochondrial oxidative metabolism and enhancing glycolysis; E2F1-knockdown in macrophage increased mitochondrial oxidative metabolism, ameliorated macrophage-mediated inflammatory endothelial injury and promoted reendothelialization repair. However, the underlying molecular mechanism is still unclear. Our whole transcriptome RNA sequencing and Chromatin Immunoprecipitation (CHIP) results showed that pyruvate dehydrogenase kinases 4(PDK4) might play a critical role in E2F1-mediated macrophage metabolism and polarization regulation. Overexpression of PDK4 can reverse the effect of E2F1-kncokdown on the modulation of macrophage function. This project will integrate multidisciplinary cross-technology of mitochondria biology, metabolomics and vascular biology to investigate the role of E2F1 in regulating macrophage proinflammatory polarization and inflammatory vascular endothelial injury through modulating mitochondrial metabolism; to search for the new therapeutic target and strategy for the prevention and treatment of vascular endothelial injury and atherosclerosis.