Control of Pathological Cardiac Hypertrophy by Transcriptional Corepressor IRF2BP2 (Interferon Regulatory Factor-2 Binding Protein 2).

Abstract

The transcription factor NFAT1 (nuclear factor of activated T-cells 1), with the aid of transcriptional coactivators, has been recognized for its necessity and sufficiency to drive pathological cardiac hypertrophy. However, how the transcriptional activity of NFAT1 in terms of cardiac hypertrophy is controlled at the transcriptional level has not been well defined. Herein, we showed that a cardiac-enriched protein IRF2BP2 (interferon regulatory factor-2 binding protein 2) was further upregulated in both human and mouse hypertrophied myocardium and negatively regulated cardiomyocyte hypertrophic response in vitro. By generating cardiomyocyte-specific Irf2bp2 knockout and Irf2bp2-transgenic mouse strains, our in vivo experiments showed that, whereas IRF2BP2 loss-of-function exacerbated both aortic banding- and angiotensin II infusion-induced cardiac hypertrophic response, IRF2BP2 overexpression exerted a strong protective effect against these maladaptive processes. Particularly, IRF2BP2 directly interacted with the C-terminal transactivation domain of NFAT1 by competing with myocyte enhancer factor-2C and disturbing their transcriptional synergism, thereby impeding NFAT1-transactivated hypertrophic transcriptome. As a result, the devastating effect of Irf2bp2 deficiency on cardiac hypertrophy was largely rescued by NFAT1 blockage. Our study, thus, defined IRF2BP2 as a novel negative regulator in controlling pathological cardiac hypertrophy at the transcriptional level.

• Authors: Jing Fang, Tianyu Li, Xuehai Zhu, Ke-Qiong Deng, Yan-Xiao Ji, Chun Fang, Xiao-Jing Zhang, Jun-Hong Guo, Peng Zhang, Hongliang Li, Xiang Wei
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 70 Issue 3 Pg. 515-523 (09 2017) ISSN: 1524-4563 [Electronic] United States
• PMID: 28716987 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 American Heart Association, Inc.

Chemical References

• IRF2BP2 protein, mouse
• NFATC Transcription Factors
• Nfatc2 protein, mouse
• Transcription Factors

Topics

• Animals
• Cardiomegaly (genetics, metabolism)
• Disease Models, Animal
• Down-Regulation (physiology)
• Gene Expression Profiling
• Mice
• Mice, Transgenic
• Myocytes, Cardiac (metabolism)
• NFATC Transcription Factors (genetics, metabolism)
• Protective Factors
• Transcription Factors (genetics, metabolism)
• Transcription, Genetic (physiology)
• Up-Regulation (physiology)