PPAR- activation fails to provide myocardial protection in ischemia and reperfusion in pigs

Xu, Ya, Michael Gen, Li Lu, Jennifer Fox, Sara O. Weiss, R. Dale Brown, Daniel Perlov, Hasan Ahmad, Peili Zhu, Clifford Greyson, Carlin S. Long, and Gregory G. Schwartz. PPARactivation fails to provide myocardial protection in ischemia and reperfusion in pigs. Am J Physiol Heart Circ Physiol 288: H1314– H1323, 2005. First published November 4, 2004; doi:10.1152/ajpheart. 00618.2004.—Peroxisome proliferator-activated receptor (PPAR)modulates substrate metabolism and inflammatory responses. In experimental rats subjected to myocardial ischemia-reperfusion (I/R), thiazolidinedione PPARactivators reduce infarct size and preserve left ventricular function. Troglitazone is the only PPARactivator that has been shown to be protective in I/R in large animals. However, because troglitazone contains both -tocopherol and thiazolidinedione moieties, whether PPARactivation 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 kg 1 day ), rosiglitazone (3 mg kg 1 day ), or -tocopherol (73 mg kg 1 day , 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, 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 -tocopherol compared with untreated pigs. Multivariate analysis indicated that presence of an -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 PPARactivation is not protective in a porcine model of myocardial I/R. Protective effects of troglitazone are attributable to its -tocopherol moiety. These findings, in conjunction with prior rat studies, suggest interspecies differences in the response to PPARactivation in the heart.