Protective Effect of Peroxisome Proliferator-Activated Receptor <i>α</i> Activation against Cardiac Ischemia-Reperfusion Injury Is Related to Upregulation of Uncoupling Protein-3

다국어 초록 (Multilingual Abstract)

<P>Activation of peroxisome proliferator-activated receptor <I>α</I> (PPAR<I>α</I>) confers cardioprotection, while its mechanism remains elusive. We investigated the protective effect of PPAR<I>α</I> 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 PPAR<I>α</I> ligand, or vehicle. WY-14643 increased UCP3 expression <I>in vivo</I>. Myocardial infarct size was decreased in the WY-14643 group (76 ± 8% versus 42 ± 12%, <I>P<0.05</I>). During reperfusion, the incidence of arrhythmia was higher in the control group compared with the WY-14643 group (9/10 versus 3/10, <I>P<0.05</I>). 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 PPAR<I>α</I> agonist WY-14643 mitigated the extent of myocardial infarction and incidence of reperfusion-induced arrhythmia. PPAR<I>α</I> activation conferred cytoprotective effect against hypoxia-reoxygenation. Associated mechanisms involved increased UCP3 expression and resultant attenuation of ROS production.</P>