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

Authors: Le, K  Li, R  Xu, S  Wu, X  Huang, H  Bao, Y  Cai, Y  Lan, T  Moss, J  Li, C  Zou, J  Shen, X  Liu, P 
Citation: Le K, etal., Arch Biochem Biophys. 2012 Feb 1;518(1):71-8. Epub 2011 Dec 16.
Pubmed: (View Article at PubMed) PMID:22198280
DOI: Full-text: DOI:10.1016/j.abb.2011.11.024

Peroxisome proliferator-activated receptor alpha (PPARalpha) has been implicated in the pathogenesis of cardiac hypertrophy, although its mechanism of action remains largely unknown. To determine the effect of PPARalpha activation on endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy and explore its molecular mechanisms, we evaluated the interaction of PPARalpha 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 PPARalpha activator, in a concentration-dependent manner, enhanced the association of NFATc4 with PPARalpha and decreased its interaction with GATA-4, in promoter complexes involved in activation of the rat brain natriuretic peptide (rBNP) gene. Effects of PPARalpha overexpression were similar to those of its activation by Fen. PPARalpha 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 PPARalpha activation on elevation of rBNP mRNA levels and ET-1-induced cardiomyocyte hypertrophy. Our results suggest that activated PPARalpha can compete with GATA-4 binding to NFATc4, thereby decreasing transactivation of NFATc4, and interfering with ET-1 induced cardiomyocyte hypertrophy.

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CRRD Object Information
CRRD ID: 5687133
Created: 2012-02-01
Species: All species
Last Modified: 2012-02-01
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.