2013 Fiscal Year Annual Research Report
致死性不整脈発生基質としての介在板リモデリングの検討
| Project/Area Number |
23591081
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| Research Institution | Kyushu University |
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Principal Investigator |
大草 知子 九州大学, 大学病院, 研究員 (00294629)
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| Keywords | intercalated disk / gap junction / adhesion junction / arrhythmia |
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| Research Abstract |
The intercellular junctions contain two complexes, adhesion junction (AJ) and connexin (Cx) gap junction (GJ). GJs provide the pathway for intercellular current flow. AJ mediates normal mechanical coupling and plays 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 studied the effects of Angiotensin II receptor blockade on intercellular junctions remodeling. Neonatal rat cardiomyocytes were cultured and subjected to RES. Conduction properties were examined by extracellular potential mapping system. Cx43 protein expression in cardiomyocytes was significantly increased after 60 min. Beta-catenin expression in total cell fraction was significantly increased after 30 min. The expression level of β-catenin in nucleus, which functions as T cell factor/lymphocyte enhancer binding factor (TCF/LEF) transcriptional activator of Cx43 and its degradation is regulated by glycogen synthase kinase 3β (GSK3β), was dramatically increased after 10 min. Conduction velocity was increased significantly by RES for 60min. Olmesartan prevented most these effects of RES. We showed an increase of phosphorylated GSK3β, which is phosphorylated by activated mitogen-activated protein kinases (MAPKs) and inhibits β-catenin degradations, was attenuated by olmesartan. The changes in β-catenin precede Cx43 GJ remodeling. Olmesartan might be a new upstream arrhythmia therapy by modulating intercellular junctions remodeling through β-catenin signaling pathway.
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