Peroxisome proliferator-activated receptor α down-regulation is associated with enhanced ceramide levels in age-associated cardiac hypertrophy

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