title: Protective Effect of Peroxisome Proliferator-Activated Receptor α Activation against Cardiac Ischemia-Reperfusion Injury Is Related to Upregulation of Uncoupling Protein-3.
abstract: Activation of peroxisome proliferator-activated receptor α (PPARα) confers cardioprotection, while its mechanism remains elusive. We investigated the protective effect of PPARα activation against cardiac ischemia-reperfusion injury in terms of the expression of uncoupling protein (UCP). Myocardial infarct size and UCP expression were measured in rats treated with WY-14643 20 mg/kg, a PPARα ligand, or vehicle. WY-14643 increased UCP3 expression in vivo. Myocardial infarct size was decreased in the WY-14643 group (76 ± 8% versus 42 ± 12%, P<0.05). During reperfusion, the incidence of arrhythmia was higher in the control group compared with the WY-14643 group (9/10 versus 3/10, P<0.05). H9c2 cells were incubated for 24 h with WY-14643 or vehicle. WY-14643 increased UCP3 expression in H9c2 cells. WY-14643 decreased hypoxia-stimulated ROS production. Cells treated with WY-14643 were more resistant to hypoxia-reoxygenation than the untreated cells. Knocking-down UCP3 by siRNA prevented WY-14643 from attenuating the production of ROS. UCP3 siRNA abolished the effect of WY-14643 on cell viability against hypoxia-reoxygenation. In summary, administration of PPARα agonist WY-14643 mitigated the extent of myocardial infarction and incidence of reperfusion-induced arrhythmia. PPARα activation conferred cytoprotective effect against hypoxia-reoxygenation. Associated mechanisms involved increased UCP3 expression and resultant attenuation of ROS production.
authors.affiliation: Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
authors.forename: Jong Wook
authors.initials: JW
authors.lastname: Song
authors.affiliation: Department of Biochemistry and Molecular Biology, Integrated Genomic Research Center for Metabolic Regulation, Institute of Genetic Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
authors.forename: Hyo Jung
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
authors.forename: Hyelin
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, Integrated Genomic Research Center for Metabolic Regulation, Institute of Genetic Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 03722, Republic of Korea.
authors.forename: Jae-woo
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
authors.forename: Young-Lan
authors.initials: YL
authors.lastname: Kwak
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000378:metabolism*; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D054059:Coronary Occlusion / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D003331:Coronary Vessels / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects; D007473:Ion Channels / Q000378:metabolism*; D008297:Male; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009203:Myocardial Infarction / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D047493:PPAR alpha / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071247:Uncoupling Protein 3; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D007473:Ion Channels; D024101:Mitochondrial Proteins; D047493:PPAR alpha; D011743:Pyrimidines; D017382:Reactive Oxygen Species; C000604394:Ucp3 protein, rat; D000071247:Uncoupling Protein 3; C006253:pirinixic acid