4.7 Article

MitoKATP channel activation suppresses gap junction permeability in the ischemic myocardium by an ERK-dependent mechanism

期刊

CARDIOVASCULAR RESEARCH
卷 70, 期 2, 页码 374-383

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OXFORD UNIV PRESS
DOI: 10.1016/j.cardiores.2006.01.023

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connexins; gap junction; ischemia; MAP kinases; preconditioning

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Background: Ischemic preconditioning accelerates suppression of gap junction (GJ) permeability during myocardial ischemia, and GJ blockers reduce infarct size. We hypothesized that the mitochondrial ATP-sensitive K+ (mitoK(ATP)) channel is one of the mechanisms regulating GJ permeability through the mitogen-activated protein kinase ERK, leading to cardioprotection. Methods and results: In isolated rabbit hearts, tissues were sampled before and after infusion of diazoxide, a selective mito(KATP) channel opener, and their intercalated disc-rich fractions were obtained for immunoblotting of mitogen-activated protein kinases. GJ permeability in the myocardium was assessed by using Lucifer yellow as a tracer of GJ communication. Infarction was induced by 30-min global ischemia/2 h reperfusion, and infarct size was expressed as a percent of area-at-risk (%IS/AR). Diazoxide (100 mu M) induced phosphorylation of ERK1/2 and (279)Ser/(282)Ser of connexin-43, a GJ subunit protein, and phospho-ERK1/2 was co-immunoprecipitated with connexin-43 in the diazoxide-treated myocardium. This ERK1/2 phosphorylation by diazoxide was inhibited by N-2-mercaptopropionyl-glycine, a free radical scavenger. Diazoxide at 10 and 100 mu M reduced intercellular transport of Lucifer yellow during ischemia by 44% and 69%, respectively, and this effect of diazoxide on GJ communication was abolished by PD98059, an ERK inhibitor. Pretreatment with 10 mu M and 100 mu M diazoxide reduced %IS/AR from 57.1 +/- 3.7% to 21.5 +/- 10.5% and 5.0 +/- 1.3%, respectively. PD98059 abolished cardioprotection by 10 mu M diazoxide but not that by 100 pM diazoxide. Conclusions: Opening of the mito(KATP) channel activates ERK1/2 via free radicals and induces ERK-mediated suppression of GJ permeability. This suppression of GJ peemeability may partly contribute to cardioprotection afforded by mito(KATP) channel activation. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

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