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

Cardiovascular Research
Kazuyuki NaitohKazuaki Shimamoto

Abstract

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. 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 microM) 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 microM reduced intercellular transport of Lucifer yellow during...Continue Reading

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