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

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

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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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