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Cardiovascular Research Advance Access [Accepted Manuscript] published online on April 27, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp132
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Cardiac PPAR{alpha} activation causes increased fatty acid oxidation, reducing efficiency and post-ischemic functional loss

Anne D. Hafstad1, Ahmed M. Khalid1, Martin Hagve1, Trine Lund1, Terje S. Larsen1, David L. Severson2, Kieran Clarke3, Rolf K. Berge4 and Ellen Aasum1

1 Department of Medical Physiology, Institute of Medical Biology, Faculty of Medicine, University of Tromsø, Tromsø, Norway
2 Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Calgary, Calgary, Alberta, T2 N 4N1, Canada
3 Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 5DG
4 The lipid research group, Institute of Medicine, University of Bergen, Norway

Correspondence to: Ellen Aasum, Department of Medical Physiology, Institute of Medical Biology, Faculty of Medicine, University of Tromsø N-9037 Tromsø, Norway. Phone: +47 77 64 67 56, Fax: +47 77 64 54 40, email: ellenaa{at}fagmed.uit.no

Aims: Myocardial fatty acid (FA) oxidation is regulated acutely by the FA supply and chronically at the transcriptional level due to FA activation of peroxisome proliferator-activated receptor-{alpha} (PPAR{alpha}). However, in vivo administration of PPAR{alpha} 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 PPAR{alpha} activity.

Methods and results: Despite the fact that TTA treatment decreased plasma concentrations of lipids (FA and triacylglycerols), hearts from TTA-treated mice showed increased mRNA expression of PPAR{alpha} target genes. Cardiac substrate utilization, ventricular function, cardiac efficiency and susceptibility to ischemia-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 PPAR{alpha}-null mice. Thus, it appears that the metabolic effects of TTA on the heart must be due to a direct stimulatory effect on cardiac PPAR{alpha}. Hearts from TTA-treated mice also showed a marked reduction in cardiac efficiency (due to a two-fold increase in unloaded myocardial oxygen consumption) and decreased recovery of ventricular contractile function following low-flow ischemia.

Conclusion: This study for the first time observed that in vivo administration of a synthetic PPAR{alpha} ligand elevated FA oxidation, an effect that was also associated with decreased cardiac efficiency and reduced post-ischemic functional recovery.

KEYWORDS cardiac metabolism; glucose oxidation; fatty acid oxidation; ischemia-reperfusion; cardiac function; cardiac efficiency; PPAR{alpha} target genes

Time for primary review: 21 Days

(Anne D. Hafstad and Ahmed M. Khalid have made equal contributions to this paper)


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