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PPARα activation inhibits endothelin-1-induced cardiomyocyte hypertrophy by prevention of NFATc4 binding to GATA-4
- Source :
- Archives of Biochemistry and Biophysics. 518:71-78
- Publication Year :
- 2012
- Publisher :
- Elsevier BV, 2012.
-
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.
- Subjects :
- Small interfering RNA
medicine.medical_specialty
Biophysics
Peroxisome proliferator-activated receptor
Cardiomegaly
Biology
Biochemistry
Article
Rats, Sprague-Dawley
Transactivation
Fenofibrate
Internal medicine
Natriuretic Peptide, Brain
medicine
Animals
Myocytes, Cardiac
PPAR alpha
RNA, Messenger
Promoter Regions, Genetic
Receptor
Molecular Biology
Cell Nucleus
chemistry.chemical_classification
Regulation of gene expression
Dose-Response Relationship, Drug
Endothelin-1
NFATC Transcription Factors
Activator (genetics)
Endothelin 1
GATA4 Transcription Factor
Rats
Endocrinology
Gene Expression Regulation
Mechanism of action
chemistry
medicine.symptom
Protein Binding
Subjects
Details
- ISSN :
- 00039861
- Volume :
- 518
- Database :
- OpenAIRE
- Journal :
- Archives of Biochemistry and Biophysics
- Accession number :
- edsair.doi.dedup.....712961308f164104b9b23102df4962f9