title: Interferon regulatory factor 3 protects against adverse neo-intima formation.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: 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.
authors.forename: Shu-Min
authors.initials: SM
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Zuo-Zhi
authors.initials: ZZ
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Pi-Xiao
authors.initials: PX
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Hou-Zao
authors.initials: HZ
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Hong-Jing
authors.initials: HJ
authors.lastname: Guan
authors.affiliation: 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.
authors.forename: Ding-Sheng
authors.initials: DS
authors.lastname: Jiang
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Song
authors.initials: S
authors.lastname: Tian
authors.affiliation: 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.
authors.forename: Da
authors.initials: D
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D058426:Neointima; D047495:PPAR gamma / Q000502:physiology
chemical_list: D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D047495:PPAR gamma
keywords: IRF3; Neo-intima formation; PPARγ; Proliferation