FKBP12 is a critical regulator of the heart rhythm and the cardiac voltage-gated sodium current in mice

Mitsunori Maruyama, Bai Yan Li, Hanying Chen, Xuehong Xu, Long Sheng Song, Silvia Guatimosim, Wuqiang Zhu, Weidong Yong, Wenjun Zhang, Guixue Bu, Shien-Fong Lin, Michael C. Fishbein, W. Jonathan Lederer, John H. Schild, Loren J. Field, Michael Rubart, Peng Sheng Chen, Weinian Shou*

*Corresponding author for this work

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Rationale: FK506 binding protein (FKBP)12 is a known cis-trans peptidyl prolyl isomerase and highly expressed in the heart. Its role in regulating postnatal cardiac function remains largely unknown. Methods and Results: We generated FKBP12 overexpressing transgenic (αMyHC-FKBP12) mice and cardiomyocyte-restricted FKBP12 conditional knockout (FKBP12 f/fαMyHC-Cre) mice and analyzed their cardiac electrophysiology in vivo and in vitro. A high incidence (38%) of sudden death was found in αMyHC-FKBP12 mice. Surface and ambulatory ECGs documented cardiac conduction defects, which were further confirmed by electric measurements and optical mapping in Langendorff-perfused hearts. αMyHC-FKBP12 hearts had slower action potential upstrokes and longer action potential durations. Whole-cell patch-clamp analyses demonstrated an ≊80% reduction in peak density of the tetrodotoxin-resistant, voltage-gated sodium current I Na in αMyHC-FKBP12 ventricular cardiomyocytes, a slower recovery of INa from inactivation, shifts of steady-state activation and inactivation curves of INa to more depolarized potentials, and augmentation of late INa, suggesting that the arrhythmogenic phenotype of αMyHC-FKBP12 mice is attributable to abnormal INa. Ventricular cardiomyocytes isolated from FKBP12f/fαMyHC-Cre hearts showed faster action potential upstrokes and a more than 2-fold increase in peak I Na density. Dialysis of exogenous recombinant FKBP12 protein into FKBP12-deficient cardiomyocytes promptly recapitulated alterations in I Na seen in αMyHC-FKBP12 myocytes. Conclusions: FKBP12 is a critical regulator of INa and is important for cardiac arrhythmogenic physiology. FKPB12-mediated dysregulation of INa may underlie clinical arrhythmias associated with FK506 administration.

Original languageEnglish
Pages (from-to)1042-1052
Number of pages11
JournalCirculation Research
Volume108
Issue number9
DOIs
StatePublished - 29 Apr 2011

Keywords

  • conduction
  • heart block
  • ion channels
  • long-QT syndrome
  • proteins

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    Maruyama, M., Li, B. Y., Chen, H., Xu, X., Song, L. S., Guatimosim, S., Zhu, W., Yong, W., Zhang, W., Bu, G., Lin, S-F., Fishbein, M. C., Lederer, W. J., Schild, J. H., Field, L. J., Rubart, M., Chen, P. S., & Shou, W. (2011). FKBP12 is a critical regulator of the heart rhythm and the cardiac voltage-gated sodium current in mice. Circulation Research, 108(9), 1042-1052. https://doi.org/10.1161/CIRCRESAHA.110.237867