Chronic activation of PPARalpha is detrimental to cardiac recovery after ischemia.
High fatty acid oxidation (FAO) rates contribute to ischemia-reperfusion injury of the myocardium. Because peroxisome proliferator-activated receptor (PPAR)alpha regulates transcription of several FAO enzymes in the heart, we examined the response of mice with cardiac-restricted overexpression of PPARalpha (MHC-PPARalpha) or whole body PPARalpha deletion including the heart (PPARalpha-/-) to myocardial ischemia-reperfusion injury. Isolated working hearts from MHC-PPARalpha and nontransgenic (NTG) littermates were subjected to no-flow global ischemia followed by reperfusion. MHC-PPARalpha 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 x g dry wt(-1) x 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 x g dry wt(-1) x min(-1); P < 0.05). In hearts from PPARalpha-/- mice, FAO was significantly lower during aerobic and reperfusion (aerobic 235 +/- 36 vs. 442 +/- 75, reperfusion 205 +/- 25 vs. 346 +/- 38 nmol x g dry wt(-1) x 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 x g dry wt(-1) x min(-1); P < 0.05). Increased FAO rates in MHC-PPARalpha 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 PPARalpha-/- hearts was not significantly different from that of WT hearts (80 +/- 8% vs. 75 +/- 9%). This study demonstrates that chronic activation of PPARalpha is detrimental to the cardiac recovery during reperfusion after ischemia.
Sambandam
Nandakumar
N
Department of Pediatrics and Pharmacology, Univ. of Alberta, Edmonton, AB, Canada.
Morabito
Dominique
D
Wagg
Cory
C
Finck
Brian N
BN
Kelly
Daniel P
DP
Lopaschuk
Gary D
GD
D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006334:Heart Function Tests; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000378:metabolism; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D047493:PPAR alpha / Q000172:deficiency / Q000378:metabolism*; D019308:Palmitic Acid / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism
D005227:Fatty Acids; D009097:Multienzyme Complexes; D047493:PPAR alpha; D019308:Palmitic Acid; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase; D005947:Glucose