Peroxisome proliferator-activated receptor alpha 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 (PPARalpha) 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 PPARalpha 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 PPARalpha and the p65 subunit of nuclear factor-kappaB (NF-kappaB) was found, suggesting that this mechanism may prevent PPARalpha from binding to its response elements. The mRNA levels of PPARalpha 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-kappaB activation in SAM-P8 heart prevents PPARalpha from binding to its response elements leading to changes in gene expression that may lead to ceramide accumulation in the aged heart.
Rodríguez-Calvo
Ricardo
R
Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, and IBUB, Faculty of Pharmacy, University of Barcelona, Spain.
Serrano
Lucía
L
Barroso
Emma
E
Coll
Teresa
T
Palomer
Xavier
X
Camins
Antoni
A
Sánchez
Rosa M
RM
Alegret
Marta
M
Merlos
Manuel
M
Pallàs
Mercè
M
Laguna
Juan C
JC
Vázquez-Carrera
Manuel
M
D000375:Aging / Q000473:pathology*; D000818:Animals; D006332:Cardiomegaly / Q000209:etiology*; D002352:Carrier Proteins / Q000378:metabolism; D002518:Ceramides / Q000032:analysis*; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation; D008297:Male; D051379:Mice; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D047493:PPAR alpha / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D051996:Transcription Factor RelA
D002352:Carrier Proteins; D002518:Ceramides; D016328:NF-kappa B; D009363:Neoplasm Proteins; D047493:PPAR alpha; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D004247:DNA