Journals of Gerontology Series A: Biological Sciences and Medical Sciences Large Type Edition
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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 62:1326-1336 (2007)
© 2007 The Gerontological Society of America

Peroxisome Proliferator-Activated Receptor {alpha} Down-Regulation Is Associated With Enhanced Ceramide Levels in Age-Associated Cardiac Hypertrophy

Ricardo Rodríguez-Calvo, Lucía Serrano, Emma Barroso, Teresa Coll, Xavier Palomer, Antoni Camins, Rosa M. Sánchez, Marta Alegret, Manuel Merlos, Mercè Pallàs, Juan C. Laguna and Manuel Vázquez-Carrera

Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, and IBUB (Institut de Biomedicina de la UB), Faculty of Pharmacy, University of Barcelona, Spain.

Address correspondence to Manuel Vázquez-Carrera, PhD, Unitat de Farmacologia. Facultat de Farmacia, Diagonal 643, E-08028 Barcelona, Spain. E-mail: mvazquezcarrera{at}ub.edu

We used an experimental murine model of accelerated aging, the senescence-accelerated mouse (SAM), to examine the effect of age-associated cardiac hypertrophy on peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) expression and activity in the heart. Senescence-accelerated prone mice (SAM-P8) showed cardiac hypertrophy compared with senescence-accelerated resistant mice (SAM-R1). Furthermore, a decrease in PPAR{alpha} messenger RNA (mRNA; 28% reduction, p <.001) and protein (47%, p <.05) levels and in PPAR DNA-binding activity was observed in SAM-P8 hearts. Increased protein–protein interaction between PPAR{alpha} and the p65 subunit of nuclear factor-{kappa}B (NF-{kappa}B) was found, suggesting that this mechanism may prevent PPAR{alpha} from binding to its response elements. The mRNA levels of PPAR{alpha} target genes involved in fatty acid use were strongly suppressed in SAM-P8, which was consistent with the accumulation of ceramide in SAM-P8 hearts (2.5-fold induction, p <.05). These findings suggest that NF-{kappa}B activation in SAM-P8 heart prevents PPAR{alpha} from binding to its response elements leading to changes in gene expression that may lead to ceramide accumulation in the aged heart.






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