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CARDIOVASCULAR

Cardioprotection of Interleukin-2 Is Mediated via -Opioid Receptors

Department of Physiology, The University of Hong Kong, Hong Kong Special Administrative Region, China (C.-M.C., M.C., S.W., T.-M.W.); and Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China (Q.X., J.T.)

We examined whether interleukin-2 (IL-2) protects the myocardium against injury induced by ischemia and reperfusion via the -opioid receptor (OR). The cardioprotective effect of IL-2 was evaluated by measuring infarct size and lactate dehydrogenase (LDH) release in response to ischemia and reperfusion in the isolated rat heart. IL-2 at an optimal dose of 50 U/ml mimicked the effect of ischemic preconditioning by reducing infarct size and LDH release. The infarct and LDH-reducing effects of IL-2 were blocked by nor-binaltorphimine (5 µM), a -OR antagonist, but not naltrindole (5 µM), a -OR antagonist known to block the action of its stimulation. Moreover, blockade of the mitochondrial ATP-sensitive potassium (mito-K_ATP) channel with a selective antagonist, 5-hydroxydecanoate (100 µM), or a nonselective antagonist of K_ATP channels, glybenclamide (100 µM), or blockade of protein kinase C (PKC) with its inhibitors chelerythrine (5 µM) or GF 109203X (10 µM) [3-[1-[3-(dimethylaminopropyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride] abolished the protective effect of IL-2. Administration of free radical scavengers N-acetylcysteine (4 mM) or N-(2-mercaptopropionyl)-glycine (1 mM) also abolished the protective effects of IL-2 and U50,488H [(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide], a selective -OR agonist. This study provides the first evidence that IL-2 confers cardioprotection against injury induced by ischemia/reperfusion. The effect of IL-2 is mediated via -OR as evidenced by -OR antagonism and similar signaling mechanisms, mito-K_ATP, PKC, and reactive oxygen species involved in the cardioprotective effects of both IL-2 and -OR stimulation.

Address correspondence to: Prof. Tak Ming Wong, Department of Physiology, 4/F, Laboratory Block, Faculty of Medicine Bldg., The University of Hong Kong, 21 Sassoon Rd., Hong Kong SAR, China. E-mail: wongtakm{at}hkucc.hku.hk

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