Reduction of palmitate-induced cardiac apoptosis by fenofibrate.
The objective of this study was to test the hypothesis that a strategy based on alteration of lipid metabolism would moderate the cellular toxicity of the C16:0 saturated fatty acid-palmitate. Cardiomyocytes from neonatal mice and embryonic chicks were treated with palmitate and both oncotic and apoptotic death were observed. Fenofibrate pretreatment, 1 microM, 24 h prior to palmitate, significantly (p < 0.05) reduced palmitate-induced apoptosis. In contrast, fenofibrate had no significant effect on palmitate-induced apoptosis when fenofibrate treatment was concomitant with palmitate. The protective effect of fenofibrate was restricted to the apoptotic population. The more potent and specific PPARalpha agonist WY 14643, 1 microM, also reduced palmitate-induced apoptosis but to a smaller extent than fenofibrate. The long pretreatment time, 24 h, was necessary to show fenofibrate's effect on apoptosis, suggesting an increase in gene transcription and protein expression. Indeed, fenofibrate increased PPARalpha expression that was mainly demonstrated in the nucleus. These data suggest a novel approach to the reduction of cardiac apoptosis by the chronic treatment with the PPARalpha agonist fenofibrate.
Kong
Jennifer Y
JY
Department of Medicine, University of British Columbia, Vancouver, Canada.
Rabkin
Simon W
SW
D000818:Animals; D000831:Animals, Newborn; D000924:Anticholesteremic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D004336:Drug Antagonism; D011345:Fenofibrate / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D051379:Mice; D032383:Myocytes, Cardiac / Q000473:pathology*; D010168:Palmitates / Q000633:toxicity*; D011743:Pyrimidines / Q000494:pharmacology
D000924:Anticholesteremic Agents; D000960:Hypolipidemic Agents; D010168:Palmitates; D011743:Pyrimidines; C006253:pirinixic acid; D011345:Fenofibrate