FKBP12 Is a Critical Regulator of the Heart Rhythm and the Cardiac Voltage-Gated Sodium Current in Mice

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.