MitoKATP channel activation suppresses gap junction permeability in the ischemic myocardium by an ERK-dependent mechanism
| Autor: | Masahiro Nishihara, Yoshihiko Ichikawa, Yuichi Nakamura, Yoshihiro Ikeda, Hironori Kobayashi, Tetsuji Miura, Takayuki Miki, Katsuhiko Ohori, Kazuaki Shimamoto, Kazuyuki Naitoh |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
medicine.medical_specialty
Cell Membrane Permeability MAP Kinase Signaling System Physiology Immunoblotting Myocardial Ischemia Ischemia Mitochondria Heart chemistry.chemical_compound Adenosine Triphosphate Physiology (medical) Internal medicine medicine Diazoxide Animals Immunoprecipitation Enzyme Inhibitors Phosphorylation Protein kinase A Flavonoids Mitogen-Activated Protein Kinase Kinases Cardioprotection Lucifer yellow Myocardium Intercellular transport Tiopronin Gap Junctions Free Radical Scavengers Free radical scavenger medicine.disease Endocrinology chemistry Connexin 43 Ischemic preconditioning Rabbits Cardiology and Cardiovascular Medicine medicine.drug |
| Zdroj: | Cardiovascular Research. 70:374-383 |
| ISSN: | 0008-6363 |
| Popis: | 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 ischemia by 44% and 69%, respectively, and this effect of diazoxide on GJ communication was abolished by PD98059, an ERK inhibitor. Pretreatment with 10 microM and 100 microM 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 microM diazoxide but not that by 100 microM diazoxide.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. |
| Databáze: | OpenAIRE |
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