Interferon regulatory factor 7 functions as a novel negative regulator of pathological cardiac hypertrophy

Ding Sheng Jiang, Yu Liu, Heng Zhou, Yan Zhang, Xiao Dong Zhang, Xiao Fei Zhang, Ke Chen, Lu Gao, Juan Peng, Hui Gong, Yingjie Chen, Qinglin Yang, Peter P. Liu, Guo Chang Fan, Yunzeng Zou, Hongliang Li

Research output: Contribution to journalArticle

51 Scopus citations

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 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 (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.

Original languageEnglish (US)
Pages (from-to)713-722
Number of pages10
JournalHypertension
Volume63
Issue number4
DOIs
StatePublished - Apr 2014

Keywords

  • cardiomegaly
  • fibrosis
  • interferon regulatory factor 7

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    Jiang, D. S., Liu, Y., Zhou, H., Zhang, Y., Zhang, X. D., Zhang, X. F., Chen, K., Gao, L., Peng, J., Gong, H., Chen, Y., Yang, Q., Liu, P. P., Fan, G. C., Zou, Y., & Li, H. (2014). Interferon regulatory factor 7 functions as a novel negative regulator of pathological cardiac hypertrophy. Hypertension, 63(4), 713-722. https://doi.org/10.1161/HYPERTENSIONAHA.113.02653