期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 496, 期 4, 页码 1250-1256出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2018.01.181
关键词
Familial hypertrophic cardiomyopathy; Ryanodine receptor type 2; Troponin T; Ca2+/calmodulin dependent kinase II
资金
- Ministry of Education in Japan [21790726, 23790856, 26670404, 16K15443, 17H04178]
- Takeda Scientific Foundation in Japan
- Kanae Foundation for the Promotion of Medical Science in Japan
- Japan Heart Foundation Research Grant
- Japanese Heart Foundation Research Grant/Novartis Grant for Research Award on Molecular and Cellular Cardiology
Aims: Cardiac Troponin T (TnT) mutation-linked familial hypertrophic cardiomyopathy (FHC) is known to cause sudden cardiac death at a young age. Here, we investigated the role of the Ca2+ release channel of the cardiac sarcoplasmic reticulum (SR), ryanodine receptor (RyR2), in the pathogenic mechanism of lethal arrhythmia in FHC-related TnT-mutated transgenic mice (TG; TnT-delta160E). Methods and results: In TG cardiomyocytes, the Ca2+ spark frequency (SpF) was much higher than that in non-TG cardiomyocytes. These differences were more pronounced in the presence of isoproterenol (ISO; 10 nM). This increase in SpF was largely reversed by a CaMKII inhibitor (KN-93), but not by a protein kinase A inhibitor (H89). CaMKII phosphorylation at Ser2814 in RyR2 was increased significantly in TG. Spontaneous Ca2+ transients (sCaTs) after cessation of a 1-5 Hz pacing, frequently observed in ISO treated TG cardiomyocytes, were also attenuated by KN-93, but not by H89. The RyR2 stabilizer dantrolene attenuated Ca2+ sparks and sCaTs in ISO-treated TG cardiomyocytes, indicating that the mutation-linked aberrant Ca2+ release is mediated by destabilized RyR2. Conclusions: In FHC-linked TnT-mutated hearts, RyR2 is susceptible to CaMKII-mediated phosphorylation, presumably because of a mutation-linked increase in diastolic [Ca2+](i), causing aberrant Ca2+ release leading to lethal arrhythmia. (C) 2018 Elsevier Inc. All rights reserved.
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