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 language | English (US) |
|---|---|
| Pages (from-to) | 1042-1052 |
| Number of pages | 11 |
| Journal | Circulation Research |
| Volume | 108 |
| Issue number | 9 |
| DOIs | |
| State | Published - Apr 29 2011 |
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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 journal › Article
}
TY - JOUR
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
UR - http://www.scopus.com/inward/record.url?scp=85027931141&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85027931141&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.110.237867
DO - 10.1161/CIRCRESAHA.110.237867
M3 - Article
AN - SCOPUS:85027931141
VL - 108
SP - 1042
EP - 1052
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 9
ER -