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

Methods and Results: In cultured neonatal rat cardiomyocytes, the selective PPARβ/δ activator L-165041 (10 μmol/L) inhibited phenylephrine (PE)-induced protein synthesis ([³H]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 PPARβ/δ 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)-κB-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-κB activation. Electrophoretic mobility shift assay (EMSA) revealed that L-165041 significantly decreased LPS-stimulated NF-κB binding activity in H9c2 myotubes. Finally, coimmunoprecipitation studies showed that L-165041 strongly enhanced the physical interaction between PPARβ/δ and the p65 subunit of NF-κB, suggesting that increased association between these two proteins is the mechanism responsible for antagonizing NF-κB activation by PPARβ/δ activators.

Conclusion: These results suggest that PPARβ/δ activation inhibits PE-induced cardiac hypertrophy and LPS-induced NF-κB activation.