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Small-conductance Ca2+-activated K+ channel activation deteriorates hypoxic ventricular arrhythmias via CaMKII in cardiac hypertrophy

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Please use this identifier to cite or link to this item:http://hdl.handle.net/2115/75062

Title: Small-conductance Ca2+-activated K+ channel activation deteriorates hypoxic ventricular arrhythmias via CaMKII in cardiac hypertrophy
Other Titles: SK channels deteriorate hypoxic ventricular arrhythmia
Authors: Tenma, Taro Browse this author
Mitsuyama, Hirofumi Browse this author
Watanabe, Masaya Browse this author
Kakutani, Naoya Browse this author
Otsuka, Yutaro Browse this author
Mizukami, Kazuya Browse this author
Kamada, Rui Browse this author
Takahashi, Masayuki Browse this author
Takada, Shingo Browse this author →KAKEN DB
Sabe, Hisataka Browse this author →KAKEN DB
Tsutsui, Hiroyuki Browse this author →KAKEN DB
Yokoshiki, Hisashi Browse this author →KAKEN DB
Keywords: Ca2+/calmodulin-dependent protein kinase II (CaMKII)
cardiac hypertrophy
myocardial hypoxia
small-conductance Ca2+-activated K+ (SK) channels
ventricular arrhythmia
Issue Date: Aug-2018
Publisher: American Physiological Society
Journal Title: American journal of physiology. Heart and circulatory physiology
Volume: 315
Issue: 2
Start Page: H262
End Page: H272
Publisher DOI: 10.1152/ajpheart.00636.2017
Abstract: The molecular and electrophysiological mechanisms of acute ischemic ventricular arrhythmias in hypertrophied hearts are not well known. We hypothesized that small-conductance Ca2+-activated K+ (SK) channels are activated during hypoxia via the Ca2+/calmodulin-dependent protein kinase II (CaMKII)-dependent pathway. We used normotensive Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs) as a model of cardiac hypertrophy. The inhibitory effects of SK channels and ATP-sensitive K+ channels on electrophysiological changes and genesis of arrhythmias during simulated global hypoxia (GH) were evaluated. Hypoxia-induced abbreviation of action potential duration (APD) occurred earlier in ventricles from SHRs versus. WKY rats. Apamin, a SK channel blocker, prevented this abbreviation in SIIRs in both the early and delayed phase of GH, whereas in WKY rats only the delayed phase was prevented. In contrast, SHRs were less sensitive to glibenclamide, a ATP-sensitive K+ channel blocker, which inhibited the APD abbreviation in both phases of GH in WKY rats. SK channel blockers (apamin and UCL-1684) reduced the incidence of hypoxia-induced sustained ventricular arrhythmias in SHRs but not in WKY rats. Among three SK channel isoforms. SK2 channels were directly coimmunoprecipitated with CaMKII phosphorylated at Thr(286) (p-CaMKII). We conclude that activation of SK channels leads to the APD abbreviation and sustained ventricular arrhythmias during simulated hypoxia, especially in hypertrophied hearts. This mechanism may result from p-CaMKII-bound SK2 channels and reveal new molecular targets to prevent lethal ventricular arrhythmias during acute hypoxia in cardiac hypertrophy. NEW & NOTEWORTHY We now show a new pathophysiological role of small-conductance Ca2+-activated K+ channels, which shorten the action potential duration and induce ventricular arrhythmias during hypoxia. We also demonstrate that small-conductance Ca2+-activated K+ channels interact with phosphorylated Ca2+/calmodulin-dependent protein kinase II at Thr(286) in hypertrophied hearts.
Type: article (author version)
URI: http://hdl.handle.net/2115/75062
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 天満 太郎

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