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is detrimental to cardiac recovery following ischemia
1 Pediatrics and Pharmacology, University of Alberta, Edmonton, Alberta, Canada; Internal Medicine, Washington University, St. Lousi, MO, USA
2 Pediatrics and Pharmacology, University of Alberta, Edmonton, Alberta, Canada
3 Internal Medicine, Washington University, St. Lousi, MO, USA
* To whom correspondence should be addressed. E-mail: gary.lopaschuk{at}ualberta.ca.
High fatty acid oxidation (FAO) rates contribute to ischemia-reperfusion injury of the myocardium. Since peroxisome proliferators-activated receptor 
(PPAR) regulates transcription of a number of fatty acid oxidative enzymes in the heart, we examined the response of mice with cardiac-restricted overexpression of PPAR (MHC-PPAR), or the whole body PPAR deletion including the heart(PPAR-/-) to myocardial ischemia-reperfusion injury. Isolated working hearts from MHC-PPAR and non-transgenic (NTG) littermates were subjected to 18 minutes of no-flow global ischemia followed by 40 minutes of reperfusion. MHC-PPAR hearts had significantly higher palmitate oxidation rates during aerobic and post-ischemic reperfusion compared with NTG control hearts (aerobic, 1479 ± 171 vs 699 ± 117; reperfusion, 1062 ± 214 vs 601 ± 70 nmol/g dry wt/min, P<0.05). Conversely, glucose oxidation in MHC-PPAR hearts was significantly lower during aerobic and post-ischemic perfusions compared to control hearts (aerobic, 225 ± 36 vs 1563 ± 165; reperfusion, 402 ± 54 vs 1758 ± 165 nmol/g dry wt/min, P<0.05). In hearts from mice with targeted deletion of PPAR gene (PPAR-/- mice), FAO was significantly lower during aerobic and post-ischemic reperfusion (aerobic, 235 ± 36 vs 442 ± 75; reperfusion, 205 ± 25 vs 346 ± 38 nmol/g dry wt/min, P<0.05) whereas glucose oxidation was significantly higher compared to wild type (WT) hearts (aerobic, 2491 ± 631 vs 901 ± 119; reperfusion, 2690 ± 562 vs 1315 ± 172 nmol/g dry wt/min). Increased FAO rates in MHC-PPAR hearts were associated with a markedly lower recovery of cardiac power (45 ± 9 % vs 71 ± 6 % of pre-ischemic levels in NTG hearts, P<0.05). In contrast, the percentage recovery of cardiac power of PPAR-/- hearts was not significantly different from that of WT hearts (80±8 vs 75±9) during reperfusion. This study demonstrates that chronic activation of PPAR is detrimental to the cardiac recovery during reperfusion following ischemia.
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