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This Article Full Text Full Text (PDF) All Versions of this Article: 290/5/H1798    most recent 00631.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Xu, Y. Articles by Schwartz, G. G. Search for Related Content PubMed PubMed Citation Articles by Xu, Y. Articles by Schwartz, G. G.

The PPAR- activator fenofibrate fails to provide myocardial protection in ischemia and reperfusion in pigs

Cardiology Section, Veterans Affairs Medical Center and University of Colorado Health Sciences Center, Denver, Colorado

Submitted 13 June 2005 ; accepted in final form 22 November 2005

Rodent studies suggest that peroxisome proliferator-activated receptor- (PPAR-) activation reduces myocardial ischemia-reperfusion (I/R) injury and infarct size; however, effects of PPAR- activation in large animal models of myocardial I/R are unknown. We determined whether chronic treatment with the PPAR- 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- in vitro and to maximal concentrations achieved in clinical use. Myocardial expression of PPAR- 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- in porcine myocardium and effects of fenofibrate on systemic metabolism, treatment with this PPAR- activator does not alter myocardial metabolic or contractile responses to I/R in pigs.

nuclear receptor; fibric acid derivative; energy metabolism; cytokine; ventricular function

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