title: IRF8 suppresses pathological cardiac remodelling by inhibiting calcineurin signalling.
abstract: Interferon regulatory factor 8 (IRF8) is known to affect the innate immune response, for example, by regulating the differentiation and function of immune cells. However, whether IRF8 can influence cardiac hypertrophy is unknown. Here we show that IRF8 levels are decreased in human dilated/hypertrophic cardiomyopathic hearts and in murine hypertrophic hearts. Mice overexpressing Irf8 specifically in the heart are resistant to aortic banding (AB)-induced cardiac hypertrophy, whereas mice lacking IRF8 either globally or specifically in cardiomyocytes develop an aggravated phenotype induced by pressure overload. Mechanistically, we show that IRF8 directly interacts with NFATc1 to prevent NFATc1 translocation and thus inhibits the hypertrophic response. Inhibition of NFATc1 ameliorates the cardiac abnormalities in IRF8(-/-) mice after AB. In contrast, constitutive activation of NFATc1 nullifies the protective effects of IRF8 on cardiac hypertrophy in IRF8-overexpressing mice. Our results indicate that IRF8 is a potential therapeutic target in pathological cardiac hypertrophy.
authors: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China [2] Cardiovascular Research Institute of Wuhan University, Wuhan 430060, China [3].
authors: Ding-Sheng
authors: DS
authors: Jiang
authors: 1] Department of Thoracic and Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China [2].
authors: Xiang
authors: X
authors: Wei
authors: College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors: Xiao-Fei
authors: XF
authors: Zhang
authors: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China [2] Cardiovascular Research Institute of Wuhan University, Wuhan 430060, China.
authors: Yu
authors: Y
authors: Liu
authors: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China [2] Cardiovascular Research Institute of Wuhan University, Wuhan 430060, China.
authors: Yan
authors: Y
authors: Zhang
authors: College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors: Ke
authors: K
authors: Chen
authors: Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
authors: Lu
authors: L
authors: Gao
authors: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China [2] Cardiovascular Research Institute of Wuhan University, Wuhan 430060, China.
authors: Heng
authors: H
authors: Zhou
authors: Department of Thoracic and Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors: Xue-Hai
authors: XH
authors: Zhu
authors: University of Ottawa Heart Institute, Ottawa, Ontario, Canada K1Y 4W7.
authors: Peter P
authors: PP
authors: Liu
authors: Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors: Wayne
authors: W
authors: Bond Lau
authors: Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors: Xinliang
authors: X
authors: Ma
authors: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University. Shanghai 200032, China.
authors: Yunzeng
authors: Y
authors: Zou
authors: College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors: Xiao-Dong
authors: XD
authors: Zhang
authors: Department of Pharmacology and Cell Biophysics, University of Cincinnati, Cincinnati, Ohio 45267, USA.
authors: Guo-Chang
authors: GC
authors: Fan
authors: 1] Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China [2] Cardiovascular Research Institute of Wuhan University, Wuhan 430060, China.
authors: Hongliang
authors: H
authors: Li
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D000099185:Interferon Regulatory Factor-8
chemical_list: D019703:Calcineurin; D050835:Interferon Regulatory Factors; D050778:NFATC Transcription Factors; D009842:Oligopeptides; D000099185:Interferon Regulatory Factor-8; C121611:VIVIT peptide