Abstract
We examined whether interleukin-2 (IL-2) protects the myocardium against injury induced by ischemia and reperfusion via the κ-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 κ-OR antagonist, but not naltrindole (5 μM), a δ-OR antagonist known to block the action of its stimulation. Moreover, blockade of the mitochondrial ATP-sensitive potassium (mito-KATP) channel with a selective antagonist, 5-hydroxydecanoate (100 μM), or a nonselective antagonist of KATP 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 κ-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 κ-OR as evidenced by κ-OR antagonism and similar signaling mechanisms, mito-KATP, PKC, and reactive oxygen species involved in the cardioprotective effects of both IL-2 and κ-OR stimulation.
Footnotes
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The study was supported by a Cardiovascular Physiology Research Fund donated by L.C.S.T. (Holdings), Ltd.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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DOI: 10.1124/jpet.103.061135.
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ABBREVIATIONS: IPC, ischemia preconditioning; OR, opioid receptor; mito-KATP, mitochondrial ATP-sensitive potassium; PKC, protein kinase C; IL-2, interleukin-2; ROS, reactive oxygen species; LVEDP, left ventricular end diastolic pressure; HR, heart rate; LVDP, left ventricular developed pressure; CF, coronary flow; NTD, naltrindole; nor-BNI, nor-binaltorphimine; 5-HD, 5-hydroxydecanoate; Gly, glybenclamide; Che, chelerythrine; NAC, N-acetylcysteine; 2-MPG, N-(2-mercaptopropionyl)-glycine; U50,488H, (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide; GF 109203X, 3-[1-[3-(dimethylaminopropyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride.
- Received October 6, 2003.
- Accepted January 26, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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