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CARDIOVASCULAR

In Vivo Activation of Peroxisome Proliferator-Activated Receptor- Protects the Heart from Ischemia/Reperfusion Injury in Zucker Fatty Rats

Department of Cardiac Biology (T.-L.Y., S.S.N., W.B., B.M.J., L.S.-B., E.H.O., R.N.W.) and Quantitative Expression and Genomic Histology (K.S.), GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania

Peroxisome proliferator-activated receptor (PPAR)- is a transcription factor that belongs to the PPAR family. PPAR- is abundantly expressed in the heart, and its role in the heart is largely unknown. We tested whether pharmacological activation of PPAR- protects the heart from ischemia/reperfusion (I/R) injury in male Zucker fatty rats, a rodent model of obesity and dyslipidemia. A highly selective PPAR- agonist, [4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl] thio]-2-methylphenoxy]acetic acid (GW0742), was administered for 7 days at 10 mg/kg/day (p.o., once a day). Ischemic injury was produced by occlusion of the left anterior descending artery for 30 min followed by reperfusion for up to 24 h. Treatment with GW0742 reduced serum levels of cardiac troponin-I and infarct size by 63% (p < 0.01) and 32% (p < 0.01), respectively, and improved left ventricular function. Treatment with GW0742 up-regulated gene expression involved in cardiac fatty acid oxidation, increased fat use in the heart, and reduced serum levels of free fatty acids. The enhanced cardiac expression of interleukin (IL)-6, IL-8, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 induced by I/R were significantly attenuated by GW0742. Treatment with GW0742 also reduced apoptotic cardiomyocytes by 34% and cardiac caspase-3 activity by 61% (both p < 0.01 versus vehicle). GW0742 differentially regulated Bcl family members, favoring cell survival, and attenuated I/R-induced cardiac mitochondrial damage. In addition, GW0742 treatment augmented the cardiac Akt signaling pathway, as reflected by enhanced phospho-3-phosphoinositide-dependent kinase-1 and p-Akt. The results indicate that activation of PPAR- protected the heart from I/R injury in Zucker fatty rats, and multiple mechanisms including amelioration of lipotoxicity, anti-inflammation, and up-regulation of prosurvival signaling contribute together to the cardioprotection.

Address correspondence to: Dr. Tian-Li Yue, Department of Cardiac Biology, GlaxoSmithKline, 709 Swedeland Rd., King of Prussia, PA 19406. E-mail: tian-li_yue{at}gsk.com