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TRANSLATIONAL PHYSIOLOGY

Chronic activation of PPAR is detrimental to cardiac recovery after ischemia

¹Cardiovascular Research Group, Department of Pediatrics and Pharmacology, University of Alberta, Edmonton, Alberta, Canada; and ²Center for Cardiovascular Research, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri

Submitted 23 March 2005 ; accepted in final form 24 August 2005

High fatty acid oxidation (FAO) rates contribute to ischemia-reperfusion injury of the myocardium. Because peroxisome proliferator-activated receptor (PPAR) regulates transcription of several FAO enzymes in the heart, we examined the response of mice with cardiac-restricted overexpression of PPAR (MHC-PPAR) or whole body PPAR deletion including the heart (PPAR^–/–) to myocardial ischemia-reperfusion injury. Isolated working hearts from MHC-PPAR and nontransgenic (NTG) littermates were subjected to no-flow global ischemia followed by reperfusion. MHC-PPAR hearts had significantly higher FAO rates during aerobic and postischemic reperfusion (aerobic 1,479 ± 171 vs. 699 ± 117, reperfusion 1,062 ± 214 vs. 601 ± 70 nmol·g dry wt^–1·min^–1; P < 0.05) and significantly lower glucose oxidation rates compared with NTG hearts (aerobic 225 ± 36 vs. 1,563 ± 165, reperfusion 402 ± 54 vs. 1,758 ± 165 nmol·g dry wt^–1·min^–1; P < 0.05). In hearts from PPAR^–/– mice, FAO was significantly lower during aerobic and reperfusion (aerobic 235 ± 36 vs. 442 ± 75, reperfusion 205 ± 25 vs. 346 ± 38 nmol·g dry wt^–1·min^–1; P < 0.05) whereas glucose oxidation was significantly higher compared with wild-type (WT) hearts (aerobic 2,491 ± 631 vs. 901 ± 119, reperfusion 2,690 ± 562 vs. 1,315 ± 172 nmol·g dry wt^–1·min^–1; P < 0.05). Increased FAO rates in MHC-PPAR hearts were associated with a markedly lower recovery of cardiac power (45 ± 9% vs. 71 ± 6% of preischemic levels in NTG hearts; P < 0.05). In contrast, the percent recovery of cardiac power of PPAR^–/– hearts was not significantly different from that of WT hearts (80 ± 8% vs. 75 ± 9%). This study demonstrates that chronic activation of PPAR is detrimental to the cardiac recovery during reperfusion after ischemia.

myocardial ischemia; reperfusion; peroxisome proliferator-activated receptor ; fatty acid oxidation; acetyl-CoA carboxylase

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