論文

査読有り 筆頭著者
2016年9月

Calmodulin/CaMKII inhibition improves intercellular communication and impulse propagation in the heart and is antiarrhythmic under conditions when fibrosis is absent

CARDIOVASCULAR RESEARCH
  • Hiroki Takanari
  • Vincent J. A. Bourgonje
  • Magda S. C. Fontes
  • Antonia J. A. Raaijmakers
  • Helen Driessen
  • John A. Jansen
  • Roel van der Nagel
  • Bart Kok
  • Leonie van Stuijvenberg
  • Mohamed Boulaksil
  • Yoshio Takemoto
  • Masatoshi Yamazaki
  • Yukiomi Tsuji
  • Haruo Honjo
  • Kaichiro Kamiya
  • Itsuo Kodama
  • Mark E. Anderson
  • Marcel A. G. van der Heyden
  • Harold V. M. van Rijen
  • Toon A. B. van Veen
  • Marc A. Vos
  • 全て表示

111
4
開始ページ
410
終了ページ
421
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1093/cvr/cvw173
出版者・発行元
OXFORD UNIV PRESS

Aim In healthy hearts, ventricular gap junctions are mainly composed by connexin43 (Cx43) and localize in the intercalated disc, enabling appropriate electrical coupling. In diseased hearts, Cx43 is heterogeneously down-regulated, whereas activity of calmodulin/calcium-calmodulin protein kinase II (CaM/CaMKII) signalling increases. It is unclear if CaM/CaMKII affects Cx43 expression/localization or impulse propagation. We analysed different models to assess this.
Methods and resultsaEuro integral AC3-I mice with CaMKII genetically inhibited were subjected to pressure overload (16 weeks, TAC vs. sham). Optical and epicardial mapping was performed on Langendorff-perfused rabbit and AC3-I hearts, respectively. Cx43 subcellular distribution from rabbit/mouse ventricles was evaluated by immunoblot after Triton X-100-based fractionation. In mice with constitutively reduced CaMKII activity (AC3-I), conduction velocity (CV) was augmented (n = 11, P < 0.01 vs. WT); in AC3-I, CV was preserved after TAC, in contrast to a reduction seen in TAC-WT mice (-20%). Cx43 expression was preserved after TAC in AC3-I mice, though arrhythmias and fibrosis were still present. In rabbits, W7 (CaM inhibitor, 10 A mu M) increased CV (6-13%, n= 6, P < 0.05), while susceptibility to arrhythmias decreased. Immunoconfocal microscopy revealed enlarged Cx43 cluster sizes at intercalated discs of those hearts. Total Cx43 did not change by W7 (n= 4), whereas Triton X-100 insoluble Cx43 increased (+21%, n= 4, P < 0.01). Similar findings were obtained in AC3-I mouse hearts when compared with control, and in cultured dog cardiomyocytes. Functional implication was shown through increased intercellular coupling in cultured neonatal rat cardiomyocytes.
ConclusionaEuro integral Both acute and chronic CaM/CaMKII inhibition improves conduction characteristics and enhances localization of Cx43 in the intercalated disc. In the absence of fibrosis, this reduced the susceptibility for arrhythmias.

リンク情報
DOI
https://doi.org/10.1093/cvr/cvw173
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/27357638
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000383851600010&DestApp=WOS_CPL
ID情報
  • DOI : 10.1093/cvr/cvw173
  • ISSN : 0008-6363
  • eISSN : 1755-3245
  • PubMed ID : 27357638
  • Web of Science ID : WOS:000383851600010

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