Shu-Min Zhang1, Li-Hua Zhu1, Zuo-Zhi Li2, Pi-Xiao Wang1, Hou-Zao Chen2, Hong-Jing Guan1, Ding-Sheng Jiang1, Ke Chen3, Xiao-Fei Zhang3, Song Tian1, Da Yang1, Xiao-Dong Zhang2, Hongliang Li4. 1. Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Jiefang Road 238, Wuhan 430060, China Cardiovascular Research Institute of Wuhan University, Wuhan, China. 2. State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 3. College of Life Sciences, Wuhan University, Wuhan, China. 4. Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Jiefang Road 238, Wuhan 430060, China Cardiovascular Research Institute of Wuhan University, Wuhan, China lihl@whu.edu.cn.
Abstract
AIMS: Vascular smooth muscle cell (VSMC) proliferation is central to the pathophysiology of neo-intima formation. Interferon regulatory factor 3 (IRF3) inhibits the growth of cancer cells and fibroblasts. However, the role of IRF3 in vascular neo-intima formation is unknown. We evaluated the protective role of IRF3 against neo-intima formation in mice and the underlying mechanisms. METHODS AND RESULTS: IRF3 expression was down-regulated in VSMCs after carotid wire injury in vivo, and in SMCs after platelet-derived growth factor (PDGF)-BB challenge in vitro. Global knockout of IRF3 (IRF3-KO) led to accelerated neo-intima formation and proliferation of VSMCs, whereas the opposite was seen in SMC-specific IRF3 transgenic mice. Mechanistically, we identified IRF3 as a novel regulator of peroxisome proliferator-activated receptor γ (PPARγ), a negative regulator of SMC proliferation after vascular injury. Binding of IRF3 to the AB domain of PPARγ in the nucleus of SMCs facilitated PPARγ transactivation, resulting in decreased proliferation cell nuclear antigen expression and suppressed proliferation. Overexpression of wild-type, but not truncated, IRF3 with a mutated IRF association domain (IAD) retained the ability to exert anti-proliferative effect. CONCLUSIONS: IRF3 inhibits VSMC proliferation and neo-intima formation after vascular injury through PPARγ activation. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Vascular smooth muscle cell (VSMC) proliferation is central to the pathophysiology of neo-intima formation. Interferon regulatory factor 3 (IRF3) inhibits the growth of cancer cells and fibroblasts. However, the role of IRF3 in vascular neo-intima formation is unknown. We evaluated the protective role of IRF3 against neo-intima formation in mice and the underlying mechanisms. METHODS AND RESULTS:IRF3 expression was down-regulated in VSMCs after carotid wire injury in vivo, and in SMCs after platelet-derived growth factor (PDGF)-BB challenge in vitro. Global knockout of IRF3 (IRF3-KO) led to accelerated neo-intima formation and proliferation of VSMCs, whereas the opposite was seen in SMC-specific IRF3transgenic mice. Mechanistically, we identified IRF3 as a novel regulator of peroxisome proliferator-activated receptor γ (PPARγ), a negative regulator of SMC proliferation after vascular injury. Binding of IRF3 to the AB domain of PPARγ in the nucleus of SMCs facilitated PPARγ transactivation, resulting in decreased proliferation cell nuclear antigen expression and suppressed proliferation. Overexpression of wild-type, but not truncated, IRF3 with a mutated IRF association domain (IAD) retained the ability to exert anti-proliferative effect. CONCLUSIONS:IRF3 inhibits VSMC proliferation and neo-intima formation after vascular injury through PPARγ activation. Published on behalf of the European Society of Cardiology. All rights reserved.