Transgenic Analysis of the Role of FKBP12.6 in Cardiac Function and Intracellular Calcium Release

被引:10
作者
Liu, Ying [1 ,2 ]
Chen, Hanying [1 ]
Ji, Guangju [3 ]
Li, Baiyan [1 ,4 ]
Mohler, Peter J. [5 ]
Zhu, Zhiming [1 ,6 ]
Yong, Weidong [1 ]
Chen, Zhuang [1 ]
Xu, Xuehong [1 ]
Xin, Hongbo [2 ]
Shou, Weinian [1 ]
机构
[1] Indiana Univ Sch Med, Dept Pediat, Riley Heart Res Inst, Riley Heart Res Ctr,Herman B Wells Ctr Pediat Res, Indianapolis, IN 46033 USA
[2] Sichuan Univ, Lab Cardiovasc Dis, W China Hosp, Chengdu 610064, Peoples R China
[3] Chinese Acad Sci, Inst Biophys, Beijing 100080, Peoples R China
[4] Harbin Med Coll, Dept Pharmacol, Harbin, Peoples R China
[5] Ohio State Univ, Dept Internal Med & Physiol & Cell Biol, Columbus, OH 43210 USA
[6] Third Mil Med Univ, Daping Hosp, Dept Hypertens & Endocrinol, Daping, Peoples R China
基金
美国国家卫生研究院;
关键词
CHANNEL RYANODINE RECEPTOR; FK506-BINDING PROTEIN FKBP12.6; HYPERTROPHY; BINDING; MOUSE; HEART; MYOCYTES; PHOSPHORYLATION; OVEREXPRESSION; EXPRESSION;
D O I
10.1089/adt.2011.0411
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
FK506 binding protein 12.6 (FKBP12.6) binds to the Ca(2+) release channel ryanodine receptor (RyR2) in cardiomyocytes and stabilizes RyR2 to prevent premature sarcoplasmic reticulum Ca(2+) release. Previously, two different mouse strains deficient in FKBP12.6 were reported to have different abnormal cardiac phenotypes. The first mutant strain displayed sex-dependent cardiac hypertrophy, while the second displayed exercise-induced cardiac arrhythmia and sudden death. In this study, we tested whether FKBP12.6-deficient mice that display hypertrophic hearts can develop exercise-induced cardiac sudden death and whether the hypertrophic heart is a direct consequence of abnormal calcium handling in mutant cardiomyocytes. Our data show that FKBP12.6-deficient mice with cardiac hypertrophy do not display exercise-induced arrhythmia and/or sudden cardiac death. To investigate the role of FKBP12.6 overexpression for cardiac function and cardiomyocyte calcium release, we generated a transgenic mouse line with cardiac specific overexpression of FKBP12.6 using alpha-myosin heavy chain (alpha MHC) promoter. MHC-FKBP12.6 mice displayed normal cardiac development and function. We demonstrated that MHC-FKBP12.6 mice are able to rescue abnormal cardiac hypertrophy and abnormal calcium release in FKBP12.6-deficient mice.
引用
收藏
页码:620 / 627
页数:8
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