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

Tenma, Taro; Mitsuyama, Hirofumi; Watanabe, Masaya et al.

American journal of physiology. Heart and circulatory physiology, 2018, 315(2), H262-H272

Permalink : https://hdl.handle.net/2115/75062

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アクセス権
open access
URI
https://hdl.handle.net/2115/75062
タイトル
Small-conductance Ca2+-activated K+ channel activation deteriorates hypoxic ventricular arrhythmias via CaMKII in cardiac hypertrophy
その他のタイトル
SK channels deteriorate hypoxic ventricular arrhythmia
著者
Tenma, Taro ; Mitsuyama, Hirofumi ; Watanabe, Masaya ; Kakutani, Naoya ; Otsuka, Yutaro ; Mizukami, Kazuya ; Kamada, Rui ; Takahashi, Masayuki ; Takada, Shingo ; Sabe, Hisataka ; Tsutsui, Hiroyuki ; Yokoshiki, Hisashi
著者名
Tenma, Taro
著者名
Mitsuyama, Hirofumi
著者名
Watanabe, Masaya
著者名
Kakutani, Naoya
著者名
Otsuka, Yutaro
著者名
Mizukami, Kazuya
著者名
Kamada, Rui
著者名
Takahashi, Masayuki
e-Rad_Researcher
60722329
著者名
Takada, Shingo
e-Rad_Researcher
40187282
著者名
Sabe, Hisataka
e-Rad_Researcher
70264017
著者名
Tsutsui, Hiroyuki
e-Rad_Researcher
40360911
著者名
Yokoshiki, Hisashi
言語
英語
キーワード
Ca2+/calmodulin-dependent protein kinase II (CaMKII)
cardiac hypertrophy
myocardial hypoxia
small-conductance Ca2+-activated K+ (SK) channels
ventricular arrhythmia
発行日
2018-08
出版者
American Physiological Society
収録物名
American journal of physiology. Heart and circulatory physiology
巻(号)
315(2)
ページ
H262-H272
抄録
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.
資源タイプ
学術雑誌論文
出版タイプ
Accepted Manuscript
PISSN
0363-6135
関連情報 (isVersionOf)
出版社版DOI
https://doi.org/10.1152/ajpheart.00636.2017