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

Mitsunori Maruyama, Bai Yan Li, Hanying Chen, Xuehong Xu, Long Sheng Song, Silvia Guatimosim, Wuqiang Zhu, Weidong Yong, Wenjun Zhang, Guixue Bu, Shien-Fong Lin, Michael C. Fishbein, W. Jonathan Lederer, John H. Schild, Loren Field, Michael Rubart-von der Lohe, Peng-Sheng Chen, Weinian Shou

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1042-1052
Number of pages11
JournalCirculation Research
Volume108
Issue number9
DOIs
StatePublished - Apr 29 2011

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Tacrolimus Binding Protein 1A
Sodium
Cardiac Myocytes
Action Potentials
Cardiac Electrophysiology
Tacrolimus Binding Proteins
Peptidylprolyl Isomerase
Tetrodotoxin
Tacrolimus
Sudden Death
Recombinant Proteins
Muscle Cells

Keywords

  • conduction
  • heart block
  • ion channels
  • long-QT syndrome
  • proteins

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

FKBP12 is a critical regulator of the heart rhythm and the cardiac voltage-gated sodium current in mice. / Maruyama, Mitsunori; Li, Bai Yan; Chen, Hanying; Xu, Xuehong; Song, Long Sheng; Guatimosim, Silvia; Zhu, Wuqiang; Yong, Weidong; Zhang, Wenjun; Bu, Guixue; Lin, Shien-Fong; Fishbein, Michael C.; Lederer, W. Jonathan; Schild, John H.; Field, Loren; Rubart-von der Lohe, Michael; Chen, Peng-Sheng; Shou, Weinian.

In: Circulation Research, Vol. 108, No. 9, 29.04.2011, p. 1042-1052.

Research output: Contribution to journalArticle

Maruyama, M, Li, BY, Chen, H, Xu, X, Song, LS, Guatimosim, S, Zhu, W, Yong, W, Zhang, W, Bu, G, Lin, S-F, Fishbein, MC, Lederer, WJ, Schild, JH, Field, L, Rubart-von der Lohe, M, Chen, P-S & Shou, W 2011, 'FKBP12 is a critical regulator of the heart rhythm and the cardiac voltage-gated sodium current in mice', Circulation Research, vol. 108, no. 9, pp. 1042-1052. https://doi.org/10.1161/CIRCRESAHA.110.237867
Maruyama, Mitsunori ; Li, Bai Yan ; Chen, Hanying ; Xu, Xuehong ; Song, Long Sheng ; Guatimosim, Silvia ; Zhu, Wuqiang ; Yong, Weidong ; Zhang, Wenjun ; Bu, Guixue ; Lin, Shien-Fong ; Fishbein, Michael C. ; Lederer, W. Jonathan ; Schild, John H. ; Field, Loren ; Rubart-von der Lohe, Michael ; Chen, Peng-Sheng ; Shou, Weinian. / FKBP12 is a critical regulator of the heart rhythm and the cardiac voltage-gated sodium current in mice. In: Circulation Research. 2011 ; Vol. 108, No. 9. pp. 1042-1052.
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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.",
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T1 - FKBP12 is a critical regulator of the heart rhythm and the cardiac voltage-gated sodium current in mice

AU - Maruyama, Mitsunori

AU - Li, Bai Yan

AU - Chen, Hanying

AU - Xu, Xuehong

AU - Song, Long Sheng

AU - Guatimosim, Silvia

AU - Zhu, Wuqiang

AU - Yong, Weidong

AU - Zhang, Wenjun

AU - Bu, Guixue

AU - Lin, Shien-Fong

AU - Fishbein, Michael C.

AU - Lederer, W. Jonathan

AU - Schild, John H.

AU - Field, Loren

AU - Rubart-von der Lohe, Michael

AU - Chen, Peng-Sheng

AU - Shou, Weinian

PY - 2011/4/29

Y1 - 2011/4/29

N2 - 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.

AB - 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.

KW - conduction

KW - heart block

KW - ion channels

KW - long-QT syndrome

KW - proteins

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