title: Ablation of Interferon Regulatory Factor 3 Protects Against Atherosclerosis in Apolipoprotein E-Deficient Mice.
abstract: 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. IRF3-/-ApoE-/-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 IRF3-/-ApoE-/-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 IRF3-/-ApoE-/-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.
authors.affiliation: 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.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Wen-Lin
authors.initials: WL
authors.lastname: Cheng
authors.affiliation: 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.
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: Pi-Xiao
authors.initials: PX
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Chun
authors.initials: C
authors.lastname: Fang
authors.affiliation: 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.
authors.forename: Xue-Yong
authors.initials: XY
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Zan
authors.initials: Z
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: She
authors.affiliation: 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. lihl@whu.edu.cn.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D001057:Apolipoproteins E; D015815:Cell Adhesion Molecules; D018925:Chemokines; D050838:Interferon Regulatory Factor-3
keywords: atherosclerosis; atherosclerotic plaque; coronary artery disease; endothelial cells; inflammation