title: Interferon regulatory factor 7 functions as a novel negative regulator of pathological cardiac hypertrophy.
abstract: Cardiac hypertrophy is a complex pathological process that involves multiple factors including inflammation and apoptosis. Interferon regulatory factor 7 (IRF7) is a multifunctional regulator that participates in immune regulation, cell differentiation, apoptosis, and oncogenesis. However, the role of IRF7 in cardiac hypertrophy remains unclear. We performed aortic banding in cardiac-specific IRF7 transgenic mice, IRF7 knockout mice, and the wild-type littermates of these mice. Our results demonstrated that IRF7 was downregulated in aortic banding-induced animal hearts and cardiomyocytes that had been treated with angiotensin II or phenylephrine for 48 hours. Accordingly, heart-specific overexpression of IRF7 significantly attenuated pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction, whereas loss of IRF7 led to opposite effects. Moreover, IRF7 protected against angiotensin II-induced cardiomyocyte hypertrophy in vitro. Mechanistically, we identified that IRF7-dependent cardioprotection was mediated through IRF7 binding to inhibitor of κB kinase-β, and subsequent nuclear factor-κB inactivation. In fact, blocking nuclear factor-κB signaling with cardiac-specific inhibitors of κBα(S32A/S36A) super-repressor transgene counteracted the adverse effect of IRF7 deficiency. Conversely, activation of nuclear factor-κB signaling via a cardiac-specific conditional inhibitor of κB kinase-β(S177E/S181E) (constitutively active) transgene negated the antihypertrophic effect of IRF7 overexpression. Our data demonstrate that IRF7 acts as a novel negative regulator of pathological cardiac hypertrophy by inhibiting nuclear factor-κB signaling and may constitute a potential therapeutic target for pathological cardiac hypertrophy.
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Jiefang Road 238, Wuhan 430060, PR China. lihl@whu.edu.cn.
authors.forename: Ding-Sheng
authors.initials: DS
authors.lastname: Jiang
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.forename: Heng
authors.initials: H
authors.lastname: Zhou
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhang
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Zhang
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.forename: Lu
authors.initials: L
authors.lastname: Gao
authors.forename: Juan
authors.initials: J
authors.lastname: Peng
authors.forename: Hui
authors.initials: H
authors.lastname: Gong
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Chen
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Yang
authors.forename: Peter P
authors.initials: PP
authors.lastname: Liu
authors.forename: Guo-Chang
authors.initials: GC
authors.lastname: Fan
authors.forename: Yunzeng
authors.initials: Y
authors.lastname: Zou
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000473:pathology* / Q000503:physiopathology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006984:Hypertrophy / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000502:physiology; D066298:In Vitro Techniques; D050839:Interferon Regulatory Factor-7 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D050839:Interferon Regulatory Factor-7; C494235:Irf7 protein, mouse; D016328:NF-kappa B; D000804:Angiotensin II; D051550:I-kappa B Kinase
keywords: cardiomegaly; fibrosis; interferon regulatory factor 7