Copyright © 2006, European Society of Cardiology
MitoKATP channel activation suppresses gap junction permeability in the ischemic myocardium by an ERK-dependent mechanism
Second Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo 060-8543, Japan
* Corresponding author. Tel.: +81 11 611 2111x3225; fax: +81 11 644 7958. Email address: miura{at}sapmed.ac.jp
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+ (mitoKATP) 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 mitoKATP 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 µM) induced phosphorylation of ERK1/2 and 279Ser/282Ser 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 µM 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 µM and 100 µM 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 µM diazoxide but not that by 100 µM diazoxide.
Conclusions Opening of the mitoKATP channel activates ERK1/2 via free radicals and induces ERK-mediated suppression of GJ permeability. This suppression of GJ permeability may partly contribute to cardioprotection afforded by mitoKATP channel activation.
KEYWORDS Connexins; Gap junction; Ischemia; MAP kinases; Preconditioning
1 These authors equally contributed to this work.
Time for primary review 29 days
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