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Circ Res. 2011 Apr 29;108(9):1042-52. doi: 10.1161/CIRCRESAHA.110.237867. Epub 2011 Mar 3.

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

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1
Department of Medicine, University School of Medicine, Indianapolis, IN 46202, USA.

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/f)/αMyHC-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 I(Na) from inactivation, shifts of steady-state activation and inactivation curves of I(Na) to more depolarized potentials, and augmentation of late I(Na), suggesting that the arrhythmogenic phenotype of αMyHC-FKBP12 mice is attributable to abnormal I(Na). Ventricular cardiomyocytes isolated from FKBP12(f/f)/αMyHC-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 I(Na) and is important for cardiac arrhythmogenic physiology. FKPB12-mediated dysregulation of I(Na) may underlie clinical arrhythmias associated with FK506 administration.

PMID:
21372286
PMCID:
PMC3092589
DOI:
10.1161/CIRCRESAHA.110.237867
[Indexed for MEDLINE]
Free PMC Article

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