Other
18 Authors
- Li BY,
- Chen H,
- Bu G,
- Guatimosim S,
- Zhu W,
- Lin SF,
- Song LS,
- Maruyama M,
- Fishbein MC,
- Rubart M,
- Yong W,
- Chen PS,
- Zhang W,
- Xu X,
- Schild JH,
- Lederer WJ,
- Field LJ,
- Shou W
| First Author | Maruyama M | Year | 2011 |
| Journal | Circ Res | Volume | 108 |
| Issue | 9 | Pages | 1042-52 |
| PubMed ID | 21372286 | Mgi Jnum | J:183588 |
| Mgi Id | MGI:5318948 | Doi | 10.1161/CIRCRESAHA.110.237867 |
| Citation | Maruyama M, et al. (2011) FKBP12 is a critical regulator of the heart rhythm and the cardiac voltage-gated sodium current in mice. Circ Res 108(9):1042-52 |
| abstractText | 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 (alphaMyHC-FKBP12) mice and cardiomyocyte-restricted FKBP12 conditional knockout (FKBP12(f/f)/alphaMyHC-Cre) mice and analyzed their cardiac electrophysiology in vivo and in vitro. A high incidence (38%) of sudden death was found in alphaMyHC-FKBP12 mice. Surface and ambulatory ECGs documented cardiac conduction defects, which were further confirmed by electric measurements and optical mapping in Langendorff-perfused hearts. alphaMyHC-FKBP12 hearts had slower action potential upstrokes and longer action potential durations. Whole-cell patch-clamp analyses demonstrated an approximately 80% reduction in peak density of the tetrodotoxin-resistant, voltage-gated sodium current I(Na) in alphaMyHC-FKBP12 ventricular cardiomyocytes, a slower recovery of I(Na) from inactivation, shifts of steady-state activation and inactivation curves of I(Na) to more depolarized potentials, and augmentation of late I(Na), suggesting that the arrhythmogenic phenotype of alphaMyHC-FKBP12 mice is attributable to abnormal I(Na). Ventricular cardiomyocytes isolated from FKBP12(f/f)/alphaMyHC-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 alphaMyHC-FKBP12 myocytes. CONCLUSIONS: FKBP12 is a critical regulator of I(Na) and is important for cardiac arrhythmogenic physiology. FKPB12-mediated dysregulation of I(Na) may underlie clinical arrhythmias associated with FK506 administration. |
