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AIMS: Myocardial fatty acid (FA) oxidation is regulated acutely by the FA supply and chronically at the transcriptional level owing to FA activation of peroxisome proliferator-activated receptor-alpha (PPARalpha). However, in vivo administration of PPARalpha ligands has not been shown to increase cardiac FA oxidation. In this study we have examined the cardiac response to in vivo administration of tetradecylthioacetic acid (TTA, 0.5% w/w added to the diet for 8 days), a PPAR agonist with primarily PPARalpha activity. METHODS AND RESULTS: Despite the fact that TTA treatment decreased plasma concentrations of lipids [FA and triacylglycerols (TG)], hearts from TTA-treated mice showed increased mRNA expression of PPARalpha target genes. Cardiac substrate utilization, ventricular function, cardiac efficiency, and susceptibility to ischaemia-reperfusion were examined in isolated perfused hearts. In accordance with the mRNA changes, myocardial FA oxidation was increased 2.5-fold with a concomitant reduction in glucose oxidation. This increase in FA oxidation was abolished in PPARalpha-null mice. Thus, it appears that the metabolic effects of TTA on the heart must be owing to a direct stimulatory effect on cardiac PPARalpha. Hearts from TTA-treated mice also showed a marked reduction in cardiac efficiency (because of a two-fold increase in unloaded myocardial oxygen consumption) and decreased recovery of ventricular contractile function following low-flow ischaemia. CONCLUSION: This study for the first time observed that in vivo administration of a synthetic PPARalpha ligand elevated FA oxidation, an effect that was also associated with decreased cardiac efficiency and reduced post-ischaemic functional recovery.

Original publication

DOI

10.1093/cvr/cvp132

Type

Journal article

Journal

Cardiovasc Res

Publication Date

01/08/2009

Volume

83

Pages

519 - 526

Keywords

Administration, Oral, Animals, Blood Glucose, Cardiovascular Agents, Disease Models, Animal, Energy Metabolism, Fatty Acids, Gene Expression Regulation, Liver, Male, Mice, Mice, Inbred BALB C, Mice, Knockout, Myocardial Contraction, Myocardial Ischemia, Myocardium, Oxidation-Reduction, Oxygen Consumption, PPAR alpha, RNA, Messenger, Recovery of Function, Sulfides, Triglycerides, Ventricular Function