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

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 (PPAR) 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 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 and the p65 subunit of nuclear factor-B (NF-B) was found, suggesting that this mechanism may prevent PPAR from binding to its response elements. The mRNA levels of PPAR 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-B activation in SAM-P8 heart prevents PPAR from binding to its response elements leading to changes in gene expression that may lead to ceramide accumulation in the aged heart.