PPARα activation inhibits endothelin-1-induced cardiomyocyte hypertrophy by prevention of NFATc4 binding to GATA-4.

Abstract

Peroxisome proliferator-activated receptor alpha (PPARα) has been implicated in the pathogenesis of cardiac hypertrophy, although its mechanism of action remains largely unknown. To determine the effect of PPARα activation on endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy and explore its molecular mechanisms, we evaluated the interaction of PPARα with nuclear factor of activated T-cells c4 (NFATc4) in nuclei of cardiomyocytes from neonatal rats in primary culture. In ET-1-stimulated cardiomyocytes, data from electrophoretic mobility-shift assays (EMSA) and co-immunoprecipitation (co-IP) revealed that fenofibrate (Fen), a PPARα activator, in a concentration-dependent manner, enhanced the association of NFATc4 with PPARα and decreased its interaction with GATA-4, in promoter complexes involved in activation of the rat brain natriuretic peptide (rBNP) gene. Effects of PPARα overexpression were similar to those of its activation by Fen. PPARα depletion by small interfering RNA abolished inhibitory effects of Fen on NFATc4 binding to GATA-4 and the rBNP DNA. Quantitative RT-PCR and confocal microscopy confirmed inhibitory effects of PPARα activation on elevation of rBNP mRNA levels and ET-1-induced cardiomyocyte hypertrophy. Our results suggest that activated PPARα can compete with GATA-4 binding to NFATc4, thereby decreasing transactivation of NFATc4, and interfering with ET-1 induced cardiomyocyte hypertrophy.

• Authors: Kang Le, Ruifang Li, Suowen Xu, Xiaoqian Wu, Heqing Huang, Yingxia Bao, Yi Cai, Tian Lan, Joel Moss, Cuixian Li, Jian Zou, Xiaoyan Shen, Peiqing Liu
• Journal: Archives of biochemistry and biophysics (Arch Biochem Biophys) Vol. 518 Issue 1 Pg. 71-8 (Feb 01 2012) ISSN: 1096-0384 [Electronic] United States
• PMID: 22198280 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Endothelin-1
• GATA4 Transcription Factor
• NFATC Transcription Factors
• PPAR alpha
• RNA, Messenger
• Natriuretic Peptide, Brain
• Fenofibrate

Topics

• Animals
• Cardiomegaly (chemically induced, metabolism, pathology)
• Cell Nucleus (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Endothelin-1 (pharmacology)
• Fenofibrate (pharmacology)
• GATA4 Transcription Factor (metabolism)
• Gene Expression Regulation (drug effects)
• Myocytes, Cardiac (drug effects, metabolism, pathology)
• NFATC Transcription Factors (metabolism)
• Natriuretic Peptide, Brain (genetics)
• PPAR alpha (metabolism)
• Promoter Regions, Genetic (drug effects)
• Protein Binding (drug effects)
• RNA, Messenger (genetics, metabolism)
• Rats
• Rats, Sprague-Dawley