Role of Interferon Regulatory Factor 4 in the Regulation of Pathological Cardiac Hypertrophy

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 61; no. 6; pp. 1193 - 1202
• Main Authors: Jiang, Ding-Sheng, Bian, Zhou-Yan, Zhang, Yan, Zhang, Shu-Min, Liu, Yi, Zhang, Rui, Chen, Yingjie, Yang, Qinglin, Zhang, Xiao-Dong, Fan, Guo-Chang, Li, Hongliang
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01.06.2013; Lippincott Williams & Wilkins
• Subjects: Animals; Animals, Newborn; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blotting, Western; Cardiology. Vascular system; Cardiomegaly - genetics; Cardiomegaly - pathology; Cardiomegaly - physiopathology; Disease Models, Animal; DNA - genetics; Gene Expression Regulation; Heart Ventricles - metabolism; Heart Ventricles - pathology; Heart Ventricles - physiopathology; Humans; Interferon Regulatory Factors - biosynthesis; Interferon Regulatory Factors - genetics; Medical sciences; Mice; Mice, Knockout; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Pharmacology. Drug treatments; Rats; Real-Time Polymerase Chain Reaction; Ventricular Pressure - physiology; Heart; Hypertension; Cytokine; Cardiovascular disease; Pressure; pressure overload; Regulation(control); CREB; Overload; IRF4; Antiviral; Interferon; Circulatory system; Transcription factor; cardiac hypertrophy; Hypertrophy; transcription factor
• DOI: 10.1161/HYPERTENSIONAHA.111.00614
• ISSN: 0194-911X

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.