title: The PPAR-alpha activator fenofibrate fails to provide myocardial protection in ischemia and reperfusion in pigs.
abstract: Rodent studies suggest that peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activation reduces myocardial ischemia-reperfusion (I/R) injury and infarct size; however, effects of PPAR-alpha activation in large animal models of myocardial I/R are unknown. We determined whether chronic treatment with the PPAR-alpha activator fenofibrate affects myocardial I/R injury in pigs. Domestic farm pigs were assigned to treatment with fenofibrate 50 mg.kg(-1).day(-1) orally or no drug treatment, and either a low-fat (4% by weight) or a high-fat (20% by weight) diet. After 4 wk, 66 pigs underwent 90 min low-flow regional myocardial ischemia and 120 min reperfusion under anesthetized open-chest conditions, resulting in myocardial stunning. The high-fat group received an infusion of triglyceride emulsion and heparin during this terminal experiment to maintain elevated arterial free fatty acid (FFA) levels. An additional 21 pigs underwent 60 min no-flow ischemia and 180 min reperfusion, resulting in myocardial infarction. Plasma concentration of fenofibric acid was similar to the EC50 for activation of PPAR-alpha in vitro and to maximal concentrations achieved in clinical use. Myocardial expression of PPAR-alpha mRNA was prominent but unaffected by fenofibrate treatment. Fenofibrate increased expression of carnitine palmitoyltransferase (CPT)-I mRNA in liver and decreased arterial FFA and lactate concentrations (each P < 0.01). However, fenofibrate did not affect myocardial CPT-I expression, substrate uptake, lipid accumulation, or contractile function during low-flow I/R in either the low- or high-fat group, nor did it affect myocardial infarct size. Despite expression of PPAR-alpha in porcine myocardium and effects of fenofibrate on systemic metabolism, treatment with this PPAR-alpha activator does not alter myocardial metabolic or contractile responses to I/R in pigs.
authors.affiliation: Cardiology Section Veterans Affairs Medical Center, Denver, CO 80220, USA.
authors.forename: Ya
authors.initials: Y
authors.lastname: Xu
authors.forename: Li
authors.initials: L
authors.lastname: Lu
authors.forename: Clifford
authors.initials: C
authors.lastname: Greyson
authors.forename: Mona
authors.initials: M
authors.lastname: Rizeq
authors.forename: Karin
authors.initials: K
authors.lastname: Nunley
authors.forename: Beata
authors.initials: B
authors.lastname: Wyatt
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bristow
authors.forename: Carlin S
authors.initials: CS
authors.lastname: Long
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D011345:Fenofibrate / Q000008:administration & dosage*; D000960:Hypolipidemic Agents / Q000008:administration & dosage; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism*; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology*; D013552:Swine; D016896:Treatment Outcome
chemical_list: D002316:Cardiotonic Agents; D016207:Cytokines; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D047495:PPAR gamma; D011345:Fenofibrate