Peroxisome proliferator-activated receptor β/δ activation inhibits hypertrophy in neonatal rat cardiomyocytes

Objective: Peroxisome proliferator-activated receptor beta/delta (PPAR beta/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 PPAR beta/delta activators in cardiac hypertrophy is not yet known. Methods and Results: In cultured neonatal rat cardiomyocytes, the selective PPAR beta/delta activator L-165041 (10 mu mol/L) inhibited phenylephrine (PE)-induced protein synthesis ([H-3]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 PPAR beta/delta agonist L-165041. Stimulation of neonatal rat cardiornyocytes with PE and embryonic rat heart-derived H9c2 cells with lipopolysaccharide (LPS) enhanced the expression of the nuclear factor (NF)-kappa B-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-kappa B activation. Electrophoretic mobility shift assay (EMSA) revealed that L-165041 significantly decreased LPS-stimulated NF-kappa B binding activity in H9c2 myotubes. Finally, coinummoprecipitation studies showed that L-165041 strongly enhanced the physical interaction between PPAR beta/delta and the p65 subunit of NF-kappa B, suggesting that increased association between these two proteins is the mechanism responsible for antagonizing NF-kappa B activation by PPAR beta/delta activators. Conclusion: These results suggest that PPAR beta/delta activation inhibits PE-induced cardiac hypertrophy and LPS-induced NF-kappa B activation. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.