title: Interferon regulatory factor 1 is required for cardiac remodeling in response to pressure overload.
abstract: Interferon regulatory factor 1 (IRF1), a critical member of the IRF family, was previously shown to be associated with the immune system and to be involved in apoptosis and tumor suppression. However, the role of IRF1 in pressure overload-induced cardiac remodeling has remained unclear. Using genetic approaches, we established a central role for the IRF1 transcription factor in the regulation of cardiac remodeling both in vivo and in vitro, and we determined the mechanism underlying this process. The expression level of IRF1 was remarkably altered in both failing human hearts and hypertrophic murine hearts. Transgenic mice with cardiac-specific IRF1 overexpression exacerbated aortic banding-induced cardiac hypertrophy, ventricular dilation, fibrosis, and dysfunction, whereas IRF1-deficient (knockout) mice exhibited a significant reduction in the hypertrophic response. Similar results were observed in a global IRF1-knockout rat model. Mechanistically, the prohypertrophic effects elicited by IRF1 in response to pathological stimuli were associated with the direct activation of inducible nitric oxide synthase (iNOS). Furthermore, we identified 1 IRF1-binding site in the promoter region of the iNOS gene, which was essential for its transcription. To examine the IRF1-iNOS axis in vivo, we generated IRF1-transgenic/iNOS-knockout mice. IRF1 exerted profoundly detrimental effects in these mice; however, these effects were nullified by iNOS ablation. These data suggest the IRF1-iNOS axis as a crucial regulator of cardiac remodeling and that IRF1 could be a potent therapeutic target for cardiac remodeling.
authors.affiliation: From the Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., L.H., H.X., X.L., N.W., H.L.); Cardiovascular Research Institute (D.-S.J., L.H., H.X., X.L., N.W., H.L.) and College of Life Sciences (J.G., X.-D.Z.), Wuhan University, Wuhan, China; Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., X.C.); Department of Thoracic and Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.W., X.Z.); and Cardiovascular Division, University of Minnesota, Minneapolis (Y.C.).
authors.forename: Ding-Sheng
authors.initials: DS
authors.lastname: Jiang
authors.affiliation: From the Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., L.H., H.X., X.L., N.W., H.L.); Cardiovascular Research Institute (D.-S.J., L.H., H.X., X.L., N.W., H.L.) and College of Life Sciences (J.G., X.-D.Z.), Wuhan University, Wuhan, China; Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., X.C.); Department of Thoracic and Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.W., X.Z.); and Cardiovascular Division, University of Minnesota, Minneapolis (Y.C.).
authors.forename: Liangpeng
authors.initials: L
authors.lastname: Li
authors.affiliation: From the Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., L.H., H.X., X.L., N.W., H.L.); Cardiovascular Research Institute (D.-S.J., L.H., H.X., X.L., N.W., H.L.) and College of Life Sciences (J.G., X.-D.Z.), Wuhan University, Wuhan, China; Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., X.C.); Department of Thoracic and Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.W., X.Z.); and Cardiovascular Division, University of Minnesota, Minneapolis (Y.C.).
authors.forename: Ling
authors.initials: L
authors.lastname: Huang
authors.affiliation: From the Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., L.H., H.X., X.L., N.W., H.L.); Cardiovascular Research Institute (D.-S.J., L.H., H.X., X.L., N.W., H.L.) and College of Life Sciences (J.G., X.-D.Z.), Wuhan University, Wuhan, China; Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., X.C.); Department of Thoracic and Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.W., X.Z.); and Cardiovascular Division, University of Minnesota, Minneapolis (Y.C.).
authors.forename: Jun
authors.initials: J
authors.lastname: Gong
authors.affiliation: From the Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., L.H., H.X., X.L., N.W., H.L.); Cardiovascular Research Institute (D.-S.J., L.H., H.X., X.L., N.W., H.L.) and College of Life Sciences (J.G., X.-D.Z.), Wuhan University, Wuhan, China; Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., X.C.); Department of Thoracic and Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.W., X.Z.); and Cardiovascular Division, University of Minnesota, Minneapolis (Y.C.).
authors.forename: Hao
authors.initials: H
authors.lastname: Xia
authors.affiliation: From the Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., L.H., H.X., X.L., N.W., H.L.); Cardiovascular Research Institute (D.-S.J., L.H., H.X., X.L., N.W., H.L.) and College of Life Sciences (J.G., X.-D.Z.), Wuhan University, Wuhan, China; Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., X.C.); Department of Thoracic and Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.W., X.Z.); and Cardiovascular Division, University of Minnesota, Minneapolis (Y.C.).
authors.forename: Xiaoxiong
authors.initials: X
authors.lastname: Liu
authors.affiliation: From the Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., L.H., H.X., X.L., N.W., H.L.); Cardiovascular Research Institute (D.-S.J., L.H., H.X., X.L., N.W., H.L.) and College of Life Sciences (J.G., X.-D.Z.), Wuhan University, Wuhan, China; Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., X.C.); Department of Thoracic and Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.W., X.Z.); and Cardiovascular Division, University of Minnesota, Minneapolis (Y.C.).
authors.forename: Nian
authors.initials: N
authors.lastname: Wan
authors.affiliation: From the Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., L.H., H.X., X.L., N.W., H.L.); Cardiovascular Research Institute (D.-S.J., L.H., H.X., X.L., N.W., H.L.) and College of Life Sciences (J.G., X.-D.Z.), Wuhan University, Wuhan, China; Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., X.C.); Department of Thoracic and Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.W., X.Z.); and Cardiovascular Division, University of Minnesota, Minneapolis (Y.C.).
authors.forename: Xiang
authors.initials: X
authors.lastname: Wei
authors.affiliation: From the Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., L.H., H.X., X.L., N.W., H.L.); Cardiovascular Research Institute (D.-S.J., L.H., H.X., X.L., N.W., H.L.) and College of Life Sciences (J.G., X.-D.Z.), Wuhan University, Wuhan, China; Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., X.C.); Department of Thoracic and Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.W., X.Z.); and Cardiovascular Division, University of Minnesota, Minneapolis (Y.C.).
authors.forename: Xuehai
authors.initials: X
authors.lastname: Zhu
authors.affiliation: From the Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., L.H., H.X., X.L., N.W., H.L.); Cardiovascular Research Institute (D.-S.J., L.H., H.X., X.L., N.W., H.L.) and College of Life Sciences (J.G., X.-D.Z.), Wuhan University, Wuhan, China; Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., X.C.); Department of Thoracic and Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.W., X.Z.); and Cardiovascular Division, University of Minnesota, Minneapolis (Y.C.).
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Chen
authors.affiliation: From the Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., L.H., H.X., X.L., N.W., H.L.); Cardiovascular Research Institute (D.-S.J., L.H., H.X., X.L., N.W., H.L.) and College of Life Sciences (J.G., X.-D.Z.), Wuhan University, Wuhan, China; Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., X.C.); Department of Thoracic and Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.W., X.Z.); and Cardiovascular Division, University of Minnesota, Minneapolis (Y.C.).
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: From the Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., L.H., H.X., X.L., N.W., H.L.); Cardiovascular Research Institute (D.-S.J., L.H., H.X., X.L., N.W., H.L.) and College of Life Sciences (J.G., X.-D.Z.), Wuhan University, Wuhan, China; Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., X.C.); Department of Thoracic and Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.W., X.Z.); and Cardiovascular Division, University of Minnesota, Minneapolis (Y.C.).
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhang
authors.affiliation: From the Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (D.-S.J., L.H., H.X., X.L., N.W., H.L.); Cardiovascular Research Institute (D.-S.J., L.H., H.X., X.L., N.W., H.L.) and College of Life Sciences (J.G., X.-D.Z.), Wuhan University, Wuhan, China; Department of Thoracic and Cardiovascular Surgery, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, China (L.L., X.C.); Department of Thoracic and Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (X.W., X.Z.); and Cardiovascular Division, University of Minnesota, Minneapolis (Y.C.). lihl@whu.edu.cn.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D006321:Heart / Q000503:physiopathology; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D050856:Interferon Regulatory Factor-1; D052247:Nitric Oxide Synthase Type II
keywords: cardiomegaly; fibrosis; interferon regulatory factor-1