title: Cardioprotection of interleukin-2 is mediated via kappa-opioid receptors.
abstract: We examined whether interleukin-2 (IL-2) protects the myocardium against injury induced by ischemia and reperfusion via the kappa-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 microM), a kappa-OR antagonist, but not naltrindole (5 microM), a delta-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 microM), or a nonselective antagonist of K(ATP) channels, glybenclamide (100 microM), or blockade of protein kinase C (PKC) with its inhibitors chelerythrine (5 microM) or GF 109203X (10 microM) [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 kappa-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 kappa-OR as evidenced by kappa-OR antagonism and similar signaling mechanisms, mito-K(ATP), PKC, and reactive oxygen species involved in the cardioprotective effects of both IL-2 and kappa-OR stimulation.
authors.affiliation: Department of Physiology, The University of Hong Kong, Hong Kong Special Administrative Region, SAR, China.
authors.forename: Chun-Mei
authors.initials: CM
authors.lastname: Cao
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xia
authors.forename: Jie
authors.initials: J
authors.lastname: Tu
authors.forename: Mai
authors.initials: M
authors.lastname: Chen
authors.forename: Song
authors.initials: S
authors.lastname: Wu
authors.forename: Tak-Ming
authors.initials: TM
authors.lastname: Wong
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000627:therapeutic use*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D009203:Myocardial Infarction / Q000209:etiology / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000150:complications; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D015221:Potassium Channels; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000502:physiology*; D015398:Signal Transduction; D013997:Time Factors; D016276:Ventricular Function / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D007376:Interleukin-2; D008565:Membrane Proteins; D015221:Potassium Channels; D017382:Reactive Oxygen Species; D017473:Receptors, Opioid, kappa; C117780:mitochondrial K(ATP) channel; D007770:L-Lactate Dehydrogenase; D011493:Protein Kinase C