title: Role of interferon regulatory factor 4 in the regulation of pathological cardiac hypertrophy.
abstract: IRF4, a member of the interferon regulatory factor (IRF) family, was previously shown to be restricted in the immune system and involved in the differentiation of immune cells. However, we interestingly observed that IRF4 was also highly expressed in both human and animal hearts. Given that several transcription factors have been shown to regulate the pathological cardiac hypertrophy, we then ask whether IRF4, as a new transcription factor, plays a critical role in pressure overload-elicited cardiac remodeling. A transgenic mouse model with cardiac-specific overexpression of IRF4 was generated and subjected to an aortic banding for 4 to 8 weeks. Our results demonstrated that overexpression of IRF4 aggravated pressure overload-triggered cardiac hypertrophy, fibrosis, and dysfunction. Conversely, IRF4 knockout mice showed an attenuated hypertrophic response to chronic pressure overload. Mechanistically, we discovered that the expression and activation of cAMP response element-binding protein (CREB) were significantly increased in IRF4-overexpressing hearts, while being greatly reduced in IRF4-KO hearts on aortic banding, compared with control hearts, respectively. Similar results were observed in ex vivo cultured neonatal rat cardiomyocytes on the treatment with angiotensin II. Inactivation of CREB by dominant-negative mutation (dnCREB) offset the IRF4-mediated hypertrophic response in angiotensin II-treated myocytes. Furthermore, we identified that the promoter region of CREB contains 3 IRF4 binding sites. Altogether, these data indicate that IRF4 functions as a necessary modulator of hypertrophic response by activating the transcription of CREB in hearts. Thus, our study suggests that IRF4 might be a novel target for the treatment of pathological cardiac hypertrophy and failure.
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA.
authors.forename: Ding-Sheng
authors.initials: DS
authors.lastname: Jiang
authors.forename: Zhou-Yan
authors.initials: ZY
authors.lastname: Bian
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shu-Min
authors.initials: SM
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Chen
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Yang
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhang
authors.forename: Guo-Chang
authors.initials: GC
authors.lastname: Fan
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D006332:Cardiomegaly / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D050835:Interferon Regulatory Factors / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D017725:Ventricular Pressure / Q000502:physiology*; D000099218:Interferon Regulatory Factor-4
chemical_list: D004247:DNA; D050835:Interferon Regulatory Factors; D000099218:Interferon Regulatory Factor-4
keywords: CREB; IRF4; cardiac hypertrophy; pressure overload; transcription factor