title: Interferon regulatory factor 9 is critical for neointima formation following vascular injury.
abstract: Interferon regulatory factor 9 (IRF9) has various biological functions and regulates cell survival; however, its role in vascular biology has not been explored. Here we demonstrate a critical role for IRF9 in mediating neointima formation following vascular injury. Notably, in mice, IRF9 ablation inhibits the proliferation and migration of vascular smooth muscle cells (VSMCs) and attenuates intimal thickening in response to injury, whereas IRF9 gain-of-function promotes VSMC proliferation and migration, which aggravates arterial narrowing. Mechanistically, we show that the transcription of the neointima formation modulator SIRT1 is directly inhibited by IRF9. Importantly, genetic manipulation of SIRT1 in smooth muscle cells or pharmacological modulation of SIRT1 activity largely reverses the neointima-forming effect of IRF9. Together, our findings suggest that IRF9 is a vascular injury-response molecule that promotes VSMC proliferation and implicate a hitherto unrecognized 'IRF9-SIRT1 axis' in vasculoproliferative pathology modulation.
authors.affiliation: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China [2] Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China.
authors.forename: Shu-Min
authors.initials: SM
authors.lastname: Zhang
authors.affiliation: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China [2] Cardiovascular Research Institute, Wuhan University, Wuhan 430060, 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, Peking Union Medical College, Beijing 100005, China.
authors.forename: Hou-Zao
authors.initials: HZ
authors.lastname: Chen
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, Peking Union Medical College, Beijing 100005, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Zhang
authors.affiliation: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China [2] Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China [2] Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China.
authors.forename: Ding-Sheng
authors.initials: DS
authors.lastname: Jiang
authors.affiliation: Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Gao
authors.affiliation: Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China.
authors.forename: Song
authors.initials: S
authors.lastname: Tian
authors.affiliation: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China [2] Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China.
authors.forename: Lang
authors.initials: L
authors.lastname: Wang
authors.affiliation: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China [2] Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China [2] Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China.
authors.forename: Pi-Xiao
authors.initials: PX
authors.lastname: Wang
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Zhang
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhang
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, Peking Union Medical College, Beijing 100005, China.
authors.forename: De-Pei
authors.initials: DP
authors.lastname: Liu
authors.affiliation: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China [2] Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D000077214:Becaplermin; D002339:Carotid Arteries / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D005263:Femoral Artery / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D058426:Neointima / Q000378:metabolism / Q000473:pathology*; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D056564:Sirtuin 1 / Q000378:metabolism; D057772:Vascular System Injuries / Q000503:physiopathology*
chemical_list: D000077214:Becaplermin; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D020780:Matrix Metalloproteinase 9; D020574:Proto-Oncogene Proteins c-sis; D056564:Sirtuin 1; C494227:IRF9 protein, human; C000595409:IRF9 protein, rat; C501830:Mmp9 protein, mouse; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; C494228:Isgf3g protein, mouse