Copyright © 2004, European Society of Cardiology
Peroxisome proliferator-activated receptor β/
activation inhibits hypertrophy in neonatal rat cardiomyocytes
aPharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, Diagonal 643, E-08028 Barcelona, Spain
bCenter for Integrative Genomics, NCCR Frontiers in Genetics, University of Lausanne, Switzerland
* Corresponding author. Tel.: +34 93 4024531; fax: +34 93 4035982. Email address: mvazquezcarrera{at}ub.edu
Objective: Peroxisome proliferator-activated receptor β/
(PPARβ/) 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/ activators in cardiac hypertrophy is not yet known.
Methods and Results: In cultured neonatal rat cardiomyocytes, the selective PPARβ/ 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/ 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)-
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-B activation. Electrophoretic mobility shift assay (EMSA) revealed that L-165041 significantly decreased LPS-stimulated NF-B binding activity in H9c2 myotubes. Finally, coimmunoprecipitation studies showed that L-165041 strongly enhanced the physical interaction between PPARβ/ and the p65 subunit of NF-B, suggesting that increased association between these two proteins is the mechanism responsible for antagonizing NF-B activation by PPARβ/ activators.
Conclusion: These results suggest that PPARβ/ activation inhibits PE-induced cardiac hypertrophy and LPS-induced NF-B activation.
KEYWORDS Cardiac hypertrophy; NF-B; L-165041; p65
Time for primary review 26 days
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