PPAR-gamma activation fails to provide myocardial protection in ischemia and reperfusion in pigs.
Peroxisome proliferator-activated receptor (PPAR)-gamma modulates substrate metabolism and inflammatory responses. In experimental rats subjected to myocardial ischemia-reperfusion (I/R), thiazolidinedione PPAR-gamma activators reduce infarct size and preserve left ventricular function. Troglitazone is the only PPAR-gamma activator that has been shown to be protective in I/R in large animals. However, because troglitazone contains both alpha-tocopherol and thiazolidinedione moieties, whether PPAR-gamma activation per se is protective in myocardial I/R in large animals remains uncertain. To address this question, 56 pigs were treated orally for 8 wk with troglitazone (75 mg x kg(-1) x day(-1)), rosiglitazone (3 mg x kg(-1) x day(-1)), or alpha-tocopherol (73 mg x kg(-1) x day(-1), equimolar to troglitazone dose) or received no treatment. Pigs were then anesthetized and subjected to 90 min of low-flow regional myocardial ischemia and 90 min of reperfusion. Myocardial expression of PPAR-gamma, determined by ribonuclease protection assay, increased with troglitazone and rosiglitazone compared with no treatment. Rosiglitazone had no significant effect on myocardial contractile function (Frank-Starling relations), substrate uptake, or expression of proinflammatory cytokines during I/R compared with untreated pigs. In contrast, preservation of myocardial contractile function and lactate uptake were greater and cytokine expression was attenuated in pigs treated with troglitazone or alpha-tocopherol compared with untreated pigs. Multivariate analysis indicated that presence of an alpha-tocopherol, but not a thiazolidinedione, moiety in the test compound was significantly related to greater contractile function and lactate uptake and lower cytokine expression during I/R. We conclude that PPAR-gamma activation is not protective in a porcine model of myocardial I/R. Protective effects of troglitazone are attributable to its alpha-tocopherol moiety. These findings, in conjunction with prior rat studies, suggest interspecies differences in the response to PPAR-gamma activation in the heart.
Xu
Ya
Y
Cardiology Section, Veterans Affairs Medical Center and University of Colorado Health Sciences Center, Denver, Colorado 80220, USA.
Gen
Michael
M
Lu
Li
L
Fox
Jennifer
J
Weiss
Sara O
SO
Brown
R Dale
RD
Perlov
Daniel
D
Ahmad
Hasan
H
Zhu
Peili
P
Greyson
Clifford
C
Long
Carlin S
CS
Schwartz
Gregory G
GG
D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D002839:Chromans / Q000097:blood / Q000494:pharmacology; D003326:Coronary Circulation / Q000502:physiology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology; D005230:Fatty Acids, Nonesterified / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D007004:Hypoglycemic Agents / Q000097:blood / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D000077154:Rosiglitazone; D034421:Sus scrofa; D045162:Thiazolidinediones / Q000097:blood / Q000494:pharmacology; D000077288:Troglitazone; D016277:Ventricular Function, Left / Q000502:physiology; D024502:alpha-Tocopherol / Q000097:blood / Q000494:pharmacology
D000975:Antioxidants; D002839:Chromans; D016207:Cytokines; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C089946:2,4-thiazolidinedione; D024502:alpha-Tocopherol; D000077288:Troglitazone