title: Rapid electrical stimulation causes alterations in cardiac intercellular junction proteins of cardiomyocytes.
abstract: The intercellular junctions contain two complexes, adhesion junctions (AJ) and connexin (Cx) gap junctions (GJs). GJs provide the pathway for intercellular current flow. AJs mediate normal mechanical coupling and play an important role in the stability of GJs. We investigated the effects of rapid electrical stimulation (RES) on cardiac intercellular junctions, especially β-catenin and Cx43 alterations. We also studied the effects of ANG II receptor blockade on intercellular junction remodeling. Neonatal rats were euthanized by decapitation, and cardiomyocytes were prepared, cultured, and subjected to RES. We used real-time PCR, western blot analysis, and immunohistochemical methods. Conduction properties were examined by an extracellular potential mapping system. Cx43 protein expression in cardiomyocytes was significantly increased after 60 min. β-Catenin expression in the total cell fraction was significantly increased after 30 min. The expression level of β-catenin in the nucleus, which functions as a T cell factor/lymphocyte enhancer binding factor transcriptional activator of Cx43 with its degradation regulated by glycogen synthase kinase-3β, was dramatically increased after 10 min. Conduction velocity was increased significantly by RES for 60 min. Olmesartan prevented most these effects of RES. We showed an increase of phosphorylated glycogen synthase kinase-3β, which is phosphorylated by activated MAPKs and inhibits β-catenin degradation, was attenuated by olmesartan. The changes in β-catenin precede Cx43 GJ remodeling and might play an important role in the formation and stability of GJs. Olmesartan might be a new upstream arrhythmia therapy by modulating intercellular junction remodeling through the β-catenin signaling pathway.
authors.affiliation: Division of Cardiology, Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan;
authors.forename: Tadamitsu
authors.initials: T
authors.lastname: Nakashima
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ohkusa
authors.forename: Yoko
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Masaaki
authors.initials: M
authors.lastname: Yoshida
authors.forename: Jong-Kook
authors.initials: JK
authors.lastname: Lee
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Mizukami
authors.forename: Masafumi
authors.initials: M
authors.lastname: Yano
mesh_terms: D000200:Action Potentials; D000818:Animals; D002478:Cells, Cultured; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D004558:Electric Stimulation; D017629:Gap Junctions / Q000378:metabolism* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D018031:Connexin 43; C580592:Gja1 protein, rat; D012333:RNA, Messenger; D051176:beta Catenin
keywords: adhesion junction; connexin43; gap junction; intercellular junction; β-catenin