Endothelin-1-induced cardiac hypertrophy is inhibited by activation of peroxisome proliferator-activated receptor-alpha partly via blockade of c-Jun NH2-terminal kinase pathway.

Abstract

BACKGROUND:

Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a lipid-activated nuclear receptor that negatively regulates the vascular inflammatory gene response by interacting with transcription factors, nuclear factor-kappaB, and AP-1. However, the roles of PPAR-alpha activators in endothelin (ET)-1-induced cardiac hypertrophy are not yet known.

METHODS AND RESULTS:

First, in cultured neonatal rat cardiomyocytes, a PPAR-alpha activator, fenofibrate (10 micromol/L), and PPAR-alpha overexpression markedly inhibited the ET-1-induced increase in protein synthesis. Second, fenofibrate markedly inhibited ET-1-induced increase in c-Jun gene expression and phosphorylation of c-Jun and JNK. These results suggest that this PPAR-alpha activator interferes with the formation and activation of AP-1 protein induced by ET-1 in cardiomyocytes. Third, fenofibrate significantly inhibited the increase of ET-1 mRNA level by ET-1, which was also confirmed by luciferase assay. Electrophoretic mobility shift assay revealed that fenofibrate significantly decreased the ET-1-stimulated or phorbol 12-myristate 13-acetate-stimulated AP-1 DNA binding activity, and the nuclear extract probe complex was supershifted by anti-c-Jun antibody. Fourth, 24 hours after aortic banding (AB) operation, fenofibrate treatment significantly inhibited left ventricular hypertrophy and hypertrophy-related gene expression pattern (ET-1, brain natriuretic peptide, and beta-myosin heavy chain mRNA) in AB rats.

CONCLUSIONS:

These results suggest that PPAR-alpha activation interferes with the signaling pathway of ET-1-induced cardiac hypertrophy through negative regulation of AP-1 binding activity, partly via inhibition of the JNK pathway in cultured cardiomyocytes. We also revealed that fenofibrate treatment inhibited left ventricle hypertrophy and phenotypic changes in cardiac gene expression in AB rats in vivo.

• Authors: Yoko Irukayama-Tomobe, Takashi Miyauchi, Satoshi Sakai, Yoshitoshi Kasuya, Takehiro Ogata, Masakatsu Takanashi, Motoyuki Iemitsu, Tatsuhiko Sudo, Katsutoshi Goto, Iwao Yamaguchi
• Journal: Circulation (Circulation) Vol. 109 Issue 7 Pg. 904-10 (Feb 24 2004) ISSN: 1524-4539 [Electronic] United States
• PMID: 14967736 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endothelin-1
• Proto-Oncogene Proteins c-fos
• Proto-Oncogene Proteins c-jun
• RNA, Messenger
• Receptors, Cytoplasmic and Nuclear
• Transcription Factor AP-1
• Transcription Factors
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinases
• Tetradecanoylphorbol Acetate
• Fenofibrate

Topics

• Animals
• Animals, Newborn
• Aorta
• Cells, Cultured (drug effects, enzymology)
• Disease Models, Animal
• Endothelin-1 (biosynthesis, genetics, toxicity)
• Fenofibrate (pharmacology)
• Genes, fos
• Genes, jun (drug effects)
• Hypertrophy, Left Ventricular (chemically induced, drug therapy, metabolism, prevention & control)
• JNK Mitogen-Activated Protein Kinases
• Ligation
• MAP Kinase Signaling System (drug effects)
• Mitogen-Activated Protein Kinases (antagonists & inhibitors, physiology)
• Myocytes, Cardiac (drug effects, enzymology)
• Phosphorylation (drug effects)
• Protein Processing, Post-Translational (drug effects)
• Proto-Oncogene Proteins c-fos (biosynthesis)
• Proto-Oncogene Proteins c-jun (biosynthesis, physiology)
• RNA, Messenger (biosynthesis)
• Rats
• Rats, Sprague-Dawley
• Receptors, Cytoplasmic and Nuclear (agonists, biosynthesis, genetics, physiology)
• Signal Transduction (drug effects)
• Tetradecanoylphorbol Acetate (pharmacology)
• Transcription Factor AP-1 (antagonists & inhibitors, metabolism)
• Transcription Factors (agonists, biosynthesis, genetics, physiology)