Published online before print October 13, 2003, doi: 10.1161/01.CIR.0000093187.42015.6C
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(Circulation. 2003;108:2393.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Activation of Peroxisome Proliferator–Activated Receptor-
Protects the Heart From Ischemia/Reperfusion Injury
From GlaxoSmithKline Pharmaceuticals, King of Prussia, Pa.
Correspondence to Tian-li Yue, PhD, Cardiovascular Pharmacology, GSK, 709 Swedeland Rd, King of Prussia, PA 19406. E-mail tian-li_yue{at}gsk.com
Received August 28, 2002; de novo received April 9, 2003; revision received July 9, 2003; accepted July 11, 2003.
Background— Peroxisome proliferator–activated receptor-
(PPAR-) is expressed in the heart and regulates genes involved in myocardial fatty acid oxidation (FAO). The role of PPAR- in acute ischemia/reperfusion myocardial injury remains unclear.
Methods and Results— The coronary arteries of male mice were ligated for 30 minutes. After reperfusion for 24 hours, ischemic and infarct sizes were determined. A highly selective and potent PPAR- agonist, GW7647, was administered by mouth for 2 days, and the third dose was given 1 hour before ischemia. GW7647 at 1 and 3 mg · kg-1 · d-1 reduced infarct size by 28% and 35%, respectively (P<0.01), and myocardial contractile dysfunction was also improved. Cardioprotection by GW7647 was completely abolished in PPAR-–null mice. Ischemia/reperfusion downregulated mRNA expression of cardiac PPAR- and FAO enzyme genes, decreased myocardial FAO enzyme activity and in vivo cardiac fat oxidation, and increased serum levels of free fatty acids. All of these changes were reversed by GW7647. Moreover, GW7647 attenuated ischemia/reperfusion-induced release of multiple proinflammatory cytokines and inhibited neutrophil accumulation and myocardial expression of matrix metalloproteinases-9 and -2. Furthermore, GW7647 inhibited nuclear factor-
B activation in the heart, accompanied by enhanced levels of inhibitor-B.
Conclusions— Activation of PPAR- protected the heart from reperfusion injury. This cardioprotection might be mediated through metabolic and antiinflammatory mechanisms. This novel effect of the PPAR- agonist could provide an added benefit to patients treated with PPAR- activators for dyslipidemia.
Key Words: receptors • ischemia • reperfusion • myocardial infarction
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