动脉粥样硬化是慢性进展性血管炎症病变，以激活内皮细胞和单核/巨噬细胞及转录因子Foxp1表达异常为特征，但其机制及交互作用尚不清楚。我们新近发现内皮和单核/巨噬细胞Foxp1特异缺失小鼠动脉粥样斑块形成明显增加，高通量RNA-seq提示内皮Foxp1缺失增加IL-1β表达，而单核/巨噬细胞Foxp1缺失导致Lox-1和MMPs显著增加，提示Foxp1在不同细胞通过不同通路调节内皮-巨噬细胞交互作用，共同参与动脉粥样硬化形成。本项目在此基础上，通过Foxp1条件敲除小鼠研究：内皮细胞Foxp1介导的IL-1β调节平滑肌细胞迁移增殖和炎症表型的转变以及单核/巨噬细胞粘附迁移；单核巨噬细胞Foxp1介导的Lox-1调节巨噬细胞摄取ox-LDL，极化成促炎细胞，上调炎症因子、MMPs和ROS；抑制IL-1β或Lox-1是否逆转Foxp1基因缺失的表型，揭示动脉粥样硬化的病理机制和治疗新靶点。

Atherosclerosis is a chronic progressive inflammatory disease manifested by activation of endothelial cells (ECs) and smooth muscle cells (SMCs), recruitment of monocytes and inflammatory cells. The transcriptional factor Foxp1 is expressed in these cells, but how Foxp1 regulates these processes in vivo is poorly characterized..EC specific Foxp1 knockout (Foxp1 ECKO) or monocyte/macrphage specific Foxp1 knockout (Foxp1 MacKO) mice bred onto Apoe deficient (Apoe-KO) hyperlipidemic mouse model to study the effect of EC and macrophage specific Foxp1 on atherogenesis. Foxp1 expression is observed in ECs and macrophages, and down-regulated in ECs of atherosclerotic plaque. Foxp1 ECKO:ApoeKO, Foxp1 MacKO:ApoeKO mutant mice display significant increases in lesion formation in aortas and aortic roots with more CD11b positive macrophages and SMA positive SMCs. .Endothelial loss of Foxp1 increases adhesion and migration of monocyte, as well as proliferation and migration of SMCs, which were pro-inflammatory e.g., with higher Mcp1 expression. IL-1β is identified as a direct target of Foxp1, and the expression of IL-1β is increased in Foxp1-deficient endothelium. Both siRNA-mediated and pharmacological inhibition of IL-1β in Foxp1-deficient endothelium might reverse the increased monocyte adhesion to ECs, migration of macrophages, proliferation and migration of SMCs and higher Mcp1 expression of SMCs. Moreover, pharmacological inhibition of IL-1β will reverse the increased atherosclerotic lesion formation in Foxp1 ECKO:ApoeKO mice..Monocyte /macrophage loss of Foxp1 increases Lox-1 (Lectin-like oxidized low-density lipoprotein receptor) expression, these residential macrophages uptake more oxLDL and are polarized to pro-inflammatory cells which secrete more cytokines, MMPs (matrix metalloproteinase) and ROS (reactive oxygen species). Lox-1 is identified as a direct target of Foxp1. siRNA-mediated inhibition of Lox-1 in Foxp1-deficient macrophage might reverse the increased uptake of oxLDL and further reverse the polarization of macrophages to pro-inflammatory cells..In conclusions, these data are the first in vivo experimental validation of an atheroprotective role for cell specific function of Foxp1 in atherogenesis, most likely through 1) regulation of monocyte adhesion, macrophage migration and smooth muscle cell proliferation and migration in atherosclerosis via IL-1β pathway; 2) regulation of macrophage uptake of oxLDL and polarization to pro-inflammatory cells via Lox-1 pathway. It advances our understanding of atherogenesis, meanwhile provides opportunities for therapeutic intervention of atherosclerotic diseases.