title: Transgenic analysis of the role of FKBP12.6 in cardiac function and intracellular calcium release.
abstract: FK506 binding protein12.6 (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 α-myosin heavy chain (αMHC) 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.
authors.affiliation: Laboratory for Cardiovascular Diseases, West-China Hospital, Sichuan University, Chengdu, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Hanying
authors.initials: H
authors.lastname: Chen
authors.forename: Guangju
authors.initials: G
authors.lastname: Ji
authors.forename: Baiyan
authors.initials: B
authors.lastname: Li
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Zhu
authors.forename: Weidong
authors.initials: W
authors.lastname: Yong
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Chen
authors.forename: Xuehong
authors.initials: X
authors.lastname: Xu
authors.forename: Hongbo
authors.initials: H
authors.lastname: Xin
authors.forename: Weinian
authors.initials: W
authors.lastname: Shou
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000502:physiology*; D022021:Tacrolimus Binding Proteins / Q000502:physiology*
chemical_list: D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B; D002118:Calcium
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