Orphan Nuclear Receptor Nur77 Inhibits Cardiac Hypertrophic Response to Beta-Adrenergic Stimulation.

Abstract

The orphan nuclear receptor Nur77 plays critical roles in cardiovascular diseases, and its expression is markedly induced in the heart after beta-adrenergic receptor (β-AR) activation. However, the functional significance of Nur77 in β-AR signaling in the heart remains unclear. By using Northern blot, Western blot, and immunofluorescent staining assays, we showed that Nur77 expression was markedly upregulated in cardiomyocytes in response to multiple hypertrophic stimuli, including isoproterenol (ISO), phenylephrine (PE), and endothelin-1 (ET-1). In a time- and dose-dependent manner, ISO increases Nur77 expression in the nuclei of cardiomyocytes. Overexpression of Nur77 markedly inhibited ISO-induced cardiac hypertrophy by inducing nuclear translocation of Nur77 in cardiomyocytes. Furthermore, cardiac overexpression of Nur77 by intramyocardial injection of Ad-Nur77 substantially inhibited cardiac hypertrophy and ameliorated cardiac dysfunction after chronic infusion of ISO in mice. Mechanistically, we demonstrated that Nur77 functionally interacts with NFATc3 and GATA4 and inhibits their transcriptional activities, which are critical for the development of cardiac hypertrophy. These results demonstrate for the first time that Nur77 is a novel negative regulator for the β-AR-induced cardiac hypertrophy through inhibiting the NFATc3 and GATA4 transcriptional pathways. Targeting Nur77 may represent a potentially novel therapeutic strategy for preventing cardiac hypertrophy and heart failure.

• Authors: Guijun Yan, Ni Zhu, Shengdong Huang, Bing Yi, Xiying Shang, Ming Chen, Nadan Wang, Guan-xin Zhang, Jennifer A Talarico, Douglas G Tilley, Erhe Gao, Jianxin Sun
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 35 Issue 19 Pg. 3312-23 (Oct 2015) ISSN: 1098-5549 [Electronic] United States
• PMID: 26195821 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• Adrenergic alpha-1 Receptor Agonists
• Endothelin-1
• GATA4 Transcription Factor
• Gata4 protein, rat
• NFATC Transcription Factors
• Nr4a1 protein, rat
• Nuclear Receptor Subfamily 4, Group A, Member 1
• Phenylephrine
• Isoproterenol

Topics

• Adrenergic alpha-1 Receptor Agonists (pharmacology)
• Animals
• Cardiomegaly (chemically induced, metabolism, pathology)
• Cells, Cultured
• Endothelin-1 (pharmacology)
• GATA4 Transcription Factor (metabolism)
• Gene Expression
• Gene Expression Regulation
• Heart Ventricles (pathology)
• Isoproterenol
• Myocytes, Cardiac (drug effects, metabolism)
• NFATC Transcription Factors (metabolism)
• Nuclear Receptor Subfamily 4, Group A, Member 1 (physiology)
• Phenylephrine (pharmacology)
• Rats, Sprague-Dawley