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

Mitsunori MARUYAMA; Bai-Yan LI; Shien-Fong LIN; Michael C FISHBEIN; W Jonathan Lederer; John H SCHILD; Loren J FIELD; Michael RUBART; Peng-Sheng CHEN; WEINIAN SHOU; HANYING CHEN; XUEHONG XU; Long-Sheng SONG; Silvia GUATIMOSIM; WUQIANG ZHU; WEIDONG YONG; WENJUN ZHANG; GUIXUE BU

doi:10.1161/CIRCRESAHA.110.237867

Back

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

Journal article

Open access

Peer reviewed

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

Mitsunori MARUYAMA, Bai-Yan LI, Shien-Fong LIN, Michael C FISHBEIN, W Jonathan Lederer, John H SCHILD, Loren J FIELD, Michael RUBART, Peng-Sheng CHEN, WEINIAN SHOU, …

Circulation research, Vol.108(9), pp.1042-1052

2011

DOI: 10.1161/CIRCRESAHA.110.237867

PMCID: PMC3092589

PMID: 21372286

Files and links (1)

url

https://doi.org/10.1161/CIRCRESAHA.110.237867View

Published (Version of record) Open Access

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 (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 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 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 attributable 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. 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.

Heart

Fundamental and applied biological sciences. Psychology

Cardiology. Vascular system

Cardiac dysrhythmias

Biological and medical sciences

Medical sciences

Vertebrates: cardiovascular system

Details

Title: Subtitle: FKBP12 Is a Critical Regulator of the Heart Rhythm and the Cardiac Voltage-Gated Sodium Current in Mice
Creators: Mitsunori MARUYAMA - Department of Medicine, Riley Heart Research Center, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States
Bai-Yan LI - Department of Pharmacology Harbin Medical University, Harbin, Heilongjiang, China
Shien-Fong LIN - Department of Medicine, Riley Heart Research Center, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States
Michael C FISHBEIN - Division of Anatomical Pathology , Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, United States
W Jonathan Lederer - Medical Biotechnology Center University of Maryland School of Medicine, Baltimore, United States
John H SCHILD - Department of Biomedical Engineering Purdue School of Engineering and Technology, Indianapolis, IN, United States
Loren J FIELD - Department of Medicine, Riley Heart Research Center, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States
Michael RUBART - Krannert Institute for Cardiology and Division of Cardiology; Department of Pediatrics, Riley Heart Research Center, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States
Peng-Sheng CHEN - Department of Medicine, Riley Heart Research Center, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States
WEINIAN SHOU - Krannert Institute for Cardiology and Division of Cardiology; Department of Pediatrics, Riley Heart Research Center, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States
HANYING CHEN - Krannert Institute for Cardiology and Division of Cardiology; Department of Pediatrics, Riley Heart Research Center, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States
XUEHONG XU - Krannert Institute for Cardiology and Division of Cardiology; Department of Pediatrics, Riley Heart Research Center, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States
Long-Sheng SONG - Medical Biotechnology Center University of Maryland School of Medicine, Baltimore, United States
Silvia GUATIMOSIM - Medical Biotechnology Center University of Maryland School of Medicine, Baltimore, United States
WUQIANG ZHU - Krannert Institute for Cardiology and Division of Cardiology; Department of Pediatrics, Riley Heart Research Center, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States
WEIDONG YONG - Krannert Institute for Cardiology and Division of Cardiology; Department of Pediatrics, Riley Heart Research Center, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States
WENJUN ZHANG - Krannert Institute for Cardiology and Division of Cardiology; Department of Pediatrics, Riley Heart Research Center, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States
GUIXUE BU - Krannert Institute for Cardiology and Division of Cardiology; Department of Pediatrics, Riley Heart Research Center, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, United States
Resource Type: Journal article
Publication Details: Circulation research, Vol.108(9), pp.1042-1052
DOI: 10.1161/CIRCRESAHA.110.237867
PMID: 21372286
PMCID: PMC3092589
NLM abbreviation: Circ Res
ISSN: 0009-7330
eISSN: 1524-4571
Publisher: Lippincott Williams & Wilkins
Language: English
Date published: 2011
Academic Unit: Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984094775702771

Metrics

30 Record Views

53 Times Cited - Web of Science