@article{35bdb540793b4bc8a531d43c031bbb92,
title = "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/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.",
keywords = "conduction, heart block, ion channels, long-QT syndrome, proteins",
author = "Mitsunori Maruyama and Li, {Bai Yan} and Hanying Chen and Xuehong Xu and Song, {Long Sheng} and Silvia Guatimosim and Wuqiang Zhu and Weidong Yong and Wenjun Zhang and Guixue Bu and Lin, {Shien Fong} and Fishbein, {Michael C.} and Lederer, {W. Jonathan} and Schild, {John H.} and Field, {Loren J.} and Michael Rubart and Chen, {Peng Sheng} and Weinian Shou",
year = "2011",
month = apr
day = "29",
doi = "10.1161/CIRCRESAHA.110.237867",
language = "English (US)",
volume = "108",
pages = "1042--1052",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "9",
}