FKBP12 is a critical regulator of the heart rhythm and the cardiac voltage-gated sodium current in mice.
FKBP12 is a critical regulator of the heart rhythm and the cardiac voltage-gated sodium current in mice.
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DOI：
10.1161/circresaha.110.237867
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发表时间：
2011-04-29
影响因子：
20.1
通讯作者：
Shou W
中科院分区：
文献类型：
--
作者：
Maruyama M;Li BY;Chen H;Xu X;Song LS;Guatimosim S;Zhu W;Yong W;Zhang W;Bu G;Lin SF;Fishbein MC;Lederer WJ;Schild JH;Field LJ;Rubart M;Chen PS;Shou W
FK506结合蛋白12 （FKBP12）是一种已知的顺式-反式肽基脯氨酸异构酶，在心脏中高度表达。它在调节出生后心脏功能中的作用在很大程度上仍然未知。我们制备了FKBP12过表达转基因（αMyHC-FKBP12）小鼠和心肌细胞限制性FKBP12条件敲除（FKBP12f/f/αMyHC-Cre）小鼠，并对其进行了体内外心脏电生理分析。αMyHC-FKBP12小鼠猝死发生率高（38%）。表面和动态心电图记录了心脏传导缺陷，并通过langendorff灌注心脏的电测量和光学成像进一步证实了这一点。αMyHC-FKBP12心脏动作电位上冲较慢，动作电位持续时间较长。全细胞膜片钳分析显示，αMyHC-FKBP12心室心肌细胞中抗河蟹毒素的电压门控钠电流（INa）的峰值密度降低约80%，INa从失活中恢复较慢，INa的稳态激活和失活曲线向更多的去极化电位移动，晚期INa增加，表明αMyHC-FKBP12小鼠的心律失常表型是由于INa异常引起的。从FKBP12f/f/αMyHC-Cre心脏分离的心室心肌细胞表现出更快的动作电位上划，峰值INa密度增加2倍以上。将外源性重组FKBP12蛋白透析到缺乏FKBP12的心肌细胞中，可迅速重现αMyHC-FKBP12心肌细胞中INa的改变。FKBP12是一种关键的INa调节因子，在心律失常生理中起重要作用。fkpb12介导的INa失调可能是与FK506给药相关的临床心律失常的基础。
FK506 binding protein 12 (FKBP12) is a known cis-trans peptidyl prolyl isomerase and highly expressed in the heart. Its role in regulating postnatal cardiac function remains largely unknown. We generated FKBP12 overexpressing transgenic (αMyHC-FKBP12) mice and cardiomyocyte-restricted FKBP12 conditional knockout (FKBP12f/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 electrical 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, INa, 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 due to abnormal INa. Ventricular cardiomyocytes isolated from FKBP12f/f/αMyHC-Cre hearts showed faster action potential upstrokes and a more than 2-fold increase in peak INa density. Dialysis of exogenous recombinant FKBP12 protein into FKBP12-deficient cardiomyocytes promptly recapitulated alterations in INa seen in αMyHC-FKBP12 myocytes. FKBP12 is a critical regulator of INa and is important to cardiac arrhythmogenic physiology. FKPB12-mediated dysregulation of INa may underlie clinical arrhythmias associated with FK506 administration.