Liu Hui, Cheng Wen-Lin, Jiang Xi, Wang Pi-Xiao, Fang Chun, Zhu Xue-Yong, Huang Zan, She Zhi-Gang, Li Hongliang
From the Department of Cardiology, Renmin Hospital of Wuhan University, China (H. Liu, W.-L.C., X.J., P.-X.W., C.F., X.-Y.Z., Z.-G.S., H. Li); and The Institute of Model Animals (H. Liu, W.-L.C., X.J., P.-X.W., C.F., X.-Y.Z., Z.-G.S., H. Li), Medical Research Institute, School of Medicine (H. Liu, W.-L.C., X.J., P.-X.W., C.F., X.-Y.Z., Z.-G.S., H. Li), Collaborative Innovation Center of Model Animal (H. Liu, W.-L.C., X.J., P.-X.W., C.F., X.-Y.Z., Z.-G.S., H. Li), Cardiovascular Research Institute (H. Liu, W.-L.C., X.J., P.-X.W., C.F., X.-Y.Z., Z.-G.S., H. Li), and College of Life Science (Z.H.), Wuhan University, China.
Hypertension. 2017 Mar;69(3):510-520. doi: 10.1161/HYPERTENSIONAHA.116.08395. Epub 2017 Jan 23.
The secretion of adhesion molecules by endothelial cells, as well as the subsequent infiltration of macrophages, determines the initiation and progression of atherosclerosis. Accumulating evidence suggests that IRF3 (interferon regulatory factor 3) is required for the induction of proinflammatory cytokines and for endothelial cell proliferation. However, the effect and underlying mechanism of IRF3 on atherogenesis remain unknown. Our results demonstrated a moderate-to-strong immunoreactivity effect associated with IRF3 in the endothelium and macrophages of the atherosclerotic plaques in patients with coronary heart disease and in hyperlipidemic mice. IRF3ApoE mice showed significantly decreased atherosclerotic lesions in the whole aorta, aortic sinus, and brachiocephalic arteries. The bone marrow transplantation further suggested that the amelioration of atherosclerosis might be attributed to the effects of IRF3 deficiency mainly in endothelial cells, as well as in macrophages. The enhanced stability of atherosclerotic plaques in IRF3ApoE mice was characterized by the reduction of necrotic core size, macrophage infiltration, and lipids, which was accompanied by increased collagen and smooth muscle cell content. Furthermore, multiple proinflammatory cytokines showed a marked decrease in IRF3ApoE mice. Mechanistically, IRF3 deficiency suppresses the secretion of VCAM-1 (vascular cell adhesion molecule 1) and the expression of ICAM-1 (intercellular adhesion molecule 1) by directly binding to the ICAM-1 promoter, which subsequently attenuates macrophage infiltration. Thus, our study suggests that IRF3 might be a potential target for the treatment of atherosclerosis development.
内皮细胞分泌黏附分子以及随后巨噬细胞的浸润，决定了动脉粥样硬化的起始和进展。越来越多的证据表明，干扰素调节因子3（IRF3）是诱导促炎细胞因子和内皮细胞增殖所必需的。然而，IRF3在动脉粥样硬化发生中的作用及潜在机制仍不清楚。我们的结果显示，在冠心病患者和高脂血症小鼠的动脉粥样硬化斑块的内皮细胞和巨噬细胞中，与IRF3相关的免疫反应呈中度至强阳性。IRF3基因敲除的载脂蛋白E小鼠在整个主动脉、主动脉窦和头臂动脉中的动脉粥样硬化病变显著减少。骨髓移植进一步表明，动脉粥样硬化的改善可能主要归因于IRF3缺乏在内皮细胞以及巨噬细胞中的作用。IRF3基因敲除的载脂蛋白E小鼠中动脉粥样硬化斑块稳定性增强的特征是坏死核心大小减小、巨噬细胞浸润减少和脂质减少，同时伴有胶原蛋白和平滑肌细胞含量增加。此外，多种促炎细胞因子在IRF3基因敲除的载脂蛋白E小鼠中显著减少。机制上，IRF3缺乏通过直接结合细胞间黏附分子1（ICAM-1）启动子来抑制血管细胞黏附分子1（VCAM-1）的分泌和ICAM-1的表达，进而减弱巨噬细胞浸润。因此，我们的研究表明，IRF3可能是治疗动脉粥样硬化发展的一个潜在靶点。
