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: Ying Liu, Hanying Chen, Guangju Ji, Baiyan Li, Peter J Mohler, Zhiming Zhu, Weidong Yong, Zhuang Chen, Xuehong Xu, Hongbo Xin, Weinian Shou
• Journal: Assay and drug development technologies (Assay Drug Dev Technol) Vol. 9 Issue 6 Pg. 620-7 (Dec 2011) ISSN: 1557-8127 [Electronic] United States
• PMID: 22087651 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © MARY ANN LIEBERT, INC.

Chemical References

• Tacrolimus Binding Proteins
• tacrolimus binding protein 1B
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Cardiomegaly (genetics, metabolism)
• Female
• Humans
• Intracellular Fluid (metabolism)
• Male
• Mice
• Mice, 129 Strain
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Myocytes, Cardiac (physiology)
• Tacrolimus Binding Proteins (physiology)