Peroxisome proliferator-activated receptor beta/delta activation inhibits hypertrophy in neonatal rat cardiomyocytes.

Abstract

OBJECTIVE:

Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) is the predominant PPAR subtype in cardiac cells and plays a prominent role in the regulation of cardiac lipid metabolism. However, the role of PPARbeta/delta activators in cardiac hypertrophy is not yet known.

METHODS AND RESULTS:

In cultured neonatal rat cardiomyocytes, the selective PPARbeta/delta activator L-165041 (10 micromol/L) inhibited phenylephrine (PE)-induced protein synthesis ([(3)H]leucine uptake), induction of the fetal-type gene atrial natriuretic factor (ANF) and cardiac myocyte size. Induction of cardiac hypertrophy by PE stimulation also led to a reduction in the transcript levels of both muscle-type carnitine palmitoyltransferase (50%, P<0.05) and pyruvatedehydrogenase kinase 4 (30%, P<0.05), and these changes were reversed in the presence of the PPARbeta/delta agonist L-165041. Stimulation of neonatal rat cardiomyocytes with PE and embryonic rat heart-derived H9c2 cells with lipopolysaccharide (LPS) enhanced the expression of the nuclear factor (NF)-kappaB-target gene monocyte chemoattractant protein 1 (MCP-1). The induction of MCP-1 was reduced in the presence of L-165041, suggesting that this compound prevented NF-kappaB activation. Electrophoretic mobility shift assay (EMSA) revealed that L-165041 significantly decreased LPS-stimulated NF-kappaB binding activity in H9c2 myotubes. Finally, coimmunoprecipitation studies showed that L-165041 strongly enhanced the physical interaction between PPARbeta/delta and the p65 subunit of NF-kappaB, suggesting that increased association between these two proteins is the mechanism responsible for antagonizing NF-kappaB activation by PPARbeta/delta activators.

CONCLUSION:

These results suggest that PPARbeta/delta activation inhibits PE-induced cardiac hypertrophy and LPS-induced NF-kappaB activation.

• Authors: Anna Planavila, Ricardo Rodríguez-Calvo, Mireia Jové, Liliane Michalik, Walter Wahli, Juan C Laguna, Manuel Vázquez-Carrera
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 65 Issue 4 Pg. 832-41 (Mar 01 2005) ISSN: 0008-6363 [Print] England
• PMID: 15721863 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(3-(2-propyl-3-hydroxy-4-acetyl)phenoxy)propyloxyphenoxy acetic acid
• Acetates
• Ccl2 protein, rat
• Chemokine CCL2
• Ligands
• Lipopolysaccharides
• NF-kappa B
• PPAR delta
• PPAR-beta
• Phenols
• Phenoxyacetates
• Phenylephrine

Topics

• Acetates (pharmacology)
• Animals
• Animals, Newborn
• Cardiomegaly (metabolism, pathology)
• Cells, Cultured
• Chemokine CCL2 (metabolism)
• Gene Expression Regulation (drug effects)
• Ligands
• Lipid Metabolism
• Lipopolysaccharides (pharmacology)
• Myocytes, Cardiac (drug effects, pathology)
• NF-kappa B (metabolism)
• PPAR delta (agonists, physiology)
• PPAR-beta (agonists, physiology)
• Phenols (pharmacology)
• Phenoxyacetates
• Phenylephrine (pharmacology)
• Rats
• Rats, Sprague-Dawley