Chronic activation of PPAR is detrimental to cardiac recovery after ischemia

Sambandam, Nandakumar, Dominique Morabito, Cory Wagg, Brian N. Finck, Daniel P. Kelly, and Gary D. Lopaschuk. Chronic activation of PPAR is detrimental to cardiac recovery after ischemia. Am J Physiol Heart Circ Physiol 290: H87–H95, 2006. First published September 9, 2005; doi:10.1152/ajpheart.00285.2005.— 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 ischemiareperfusion 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 ; 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 ; 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 ; 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 ; 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.