Interferon Regulatory Factor 1 Is Required for Cardiac Remodeling in Response to Pressure Overload

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 64; no. 1; pp. 77 - 86
• Main Authors: Jiang, Ding-Sheng, Li, Liangpeng, Huang, Ling, Gong, Jun, Xia, Hao, Liu, Xiaoxiong, Wan, Nian, Wei, Xiang, Zhu, Xuehai, Chen, Yingjie, Chen, Xin, Zhang, Xiao-Dong, Li, Hongliang
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01.07.2014; Lippincott Williams & Wilkins
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiomegaly - genetics; Cardiomegaly - metabolism; Cardiomegaly - physiopathology; Disease Models, Animal; Heart - physiopathology; Heart Failure - genetics; Heart Failure - metabolism; Humans; Interferon Regulatory Factor-1 - genetics; Interferon Regulatory Factor-1 - metabolism; Medical sciences; Mice; Mice, Knockout; Mice, Transgenic; Myocardium - metabolism; Myocytes, Cardiac - metabolism; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - metabolism; Pharmacology. Drug treatments; Signal Transduction - physiology; Ventricular Remodeling - physiology; Heart; Hypertension; Cytokine; Cardiovascular disease; cardiomegaly; Pressure; Vascular remodeling; Response; Regulation(control); Overload; Fibrosis; Antiviral; Interferon; Circulatory system; interferon regulatory factor-1; fibrosis
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.114.03229

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.