Correction of impaired calmodulin binding to RyR2 as a novel therapy for lethal arrhythmia in the pressure-overloaded heart failure

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• 作者：Takayoshi Kato ; MD^* ; Takeshi Yamamoto ; MD ; PhD^&dagger ; ; ^{kenyama@yamaguchi-u.ac.jp} ; Yoshihide Nakamura ; MD^* ; Takuma Nanno ; MD^* ; Go Fukui ; MD^* ; Yoko Sufu ; MD^* ; Yoriomi Hamada ; MD^* ; Takako Maeda ; MD^* ; Shigehiko Nishimura ; MD^* ; Hironori Ishiguchi ; MD^* ; Wakako Murakami ; MD^* ; Masakazu Fukuda ; MD ; PhD^* ; Xiaojuan Xu ; MD ; PhD^* ; Akihiro Hino ; MD ; PhD^* ; Makoto Ono ; MD ; PhD^* ; Tetsuro Oda ; MD ; PhD^* ; Shinichi Okuda ; MD ; PhD^* ; Shigeki Kobayashi ; MD ; PhD^* ; Noritaka Koseki ; BS^&Dagger ; ; Hiroyuki Kyushiki ; PhD^&Dagger ; ; Masafumi Yano ; MD ; PhD^*
• 关键词：Calmodulin ; Ryanodine receptor ; Sarcoplasmic reticulum ; Calcium ; Pressure overload
• 刊名：Heart Rhythm
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：14
• 期：1
• 页码：120-127
• 全文大小：3641 K
• 卷排序：14

文摘

Calmodulin (CaM) is a key modulator of the channel gating function of the ryanodine receptor (RyR).ObjectiveThe purpose of this study was to investigate the pathogenic role of RyR-bound CaM in diastolic Ca2+ leakage from the sarcoplasmic reticulum and arrhythmogenesis in pressure-overloaded heart failure.MethodsPressure overload was induced in 12-week-old mice by transverse aortic constriction (TAC) using a 27-gauge needle.ResultsTAC operation for 8 weeks produced a significant increase in left ventricular end-diastolic diameter and frequent occurrence of lethal arrhythmias after infusion of epinephrine and caffeine in TAC mice. The amount of RyR-bound CaM decreased significantly in TAC mice compared with sham mice. The apparent affinity of CaM binding to RyR decreased in pressure-overloaded cells compared with sham cells and untreated cells. High-affinity calmodulin (HA-CaM; ie, CaM whose binding affinity to RyR was significantly increased) restored a normal level of CaM-RyR binding properties in pressure-overloaded cells. HA-CaM corrected abnormally increased Ca2+ spark frequency in the pressure-overloaded cells to the level seen in the sham cells. The frequency of spontaneous Ca2+ transients in TAC cells during and after 1–5 Hz of field stimulation was 44%, whereas it was significantly attenuated by HA-CaM but not with CaM.ConclusionSeveral disorders in the RyR channel function characteristic of pressure-overloaded cells (increased spontaneous Ca2+ leakage, delayed afterdepolarization, triggered activity, Ca2+ spark frequency, spontaneous Ca2+ transients) are caused by deteriorated CaM binding to RyR2. These disorders could be rectified by restoring normal CaM binding to RyR2.