title: Correction of impaired calmodulin binding to RyR2 as a novel therapy for lethal arrhythmia in the pressure-overloaded heart failure.
abstract: Calmodulin (CaM) is a key modulator of the channel gating function of the ryanodine receptor (RyR).
  
  
  
  The 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.
  
  
  
  Pressure overload was induced in 12-week-old mice by transverse aortic constriction (TAC) using a 27-gauge needle.
  
  
  
  TAC 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.
  
  
  
  Several 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.
authors: Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors: Takayoshi
authors: T
authors: Kato
authors: Faculty of Health Sciences, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan,. Electronic address: kenyama@yamaguchi-u.ac.jp.
authors: Takeshi
authors: T
authors: Yamamoto
authors: Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors: Yoshihide
authors: Y
authors: Nakamura
authors: Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors: Takuma
authors: T
authors: Nanno
authors: Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors: Go
authors: G
authors: Fukui
authors: Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors: Yoko
authors: Y
authors: Sufu
authors: Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors: Yoriomi
authors: Y
authors: Hamada
authors: Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors: Takako
authors: T
authors: Maeda
authors: Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors: Shigehiko
authors: S
authors: Nishimura
authors: Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors: Hironori
authors: H
authors: Ishiguchi
authors: Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors: Wakako
authors: W
authors: Murakami
authors: Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors: Masakazu
authors: M
authors: Fukuda
authors: Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors: Xiaojuan
authors: X
authors: Xu
authors: Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors: Akihiro
authors: A
authors: Hino
authors: Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors: Makoto
authors: M
authors: Ono
authors: Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors: Tetsuro
authors: T
authors: Oda
authors: Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors: Shinichi
authors: S
authors: Okuda
authors: Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors: Shigeki
authors: S
authors: Kobayashi
authors: First Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors: Noritaka
authors: N
authors: Koseki
authors: First Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors: Hiroyuki
authors: H
authors: Kyushiki
authors: Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors: Masafumi
authors: M
authors: Yano
mesh_terms: D000818:Animals; D018780:Body Surface Potential Mapping / Q000379:methods; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling; D002147:Calmodulin / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006333:Heart Failure / Q000000981:diagnostic imaging* / Q000401:mortality / Q000628:therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D032383:Myocytes, Cardiac / Q000378:metabolism; D011897:Random Allocation; D012016:Reference Values; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D012680:Sensitivity and Specificity; D017180:Tachycardia, Ventricular / Q000175:diagnosis* / Q000401:mortality / Q000628:therapy
chemical_list: D015220:Calcium Channels; D002147:Calmodulin; D019837:Ryanodine Receptor Calcium Release Channel
keywords: Calcium; Calmodulin; Pressure overload; Ryanodine receptor; Sarcoplasmic reticulum