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http://purl.uniprot.org/citations/21372286http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/21372286http://www.w3.org/2000/01/rdf-schema#comment"

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/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 I(Na) in αMyHC-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 αMyHC-FKBP12 mice is attributable to abnormal I(Na). Ventricular cardiomyocytes isolated from FKBP12(f/f)/αMyHC-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 I(Na) and is important for cardiac arrhythmogenic physiology. FKPB12-mediated dysregulation of I(Na) may underlie clinical arrhythmias associated with FK506 administration."xsd:string
http://purl.uniprot.org/citations/21372286http://purl.org/dc/terms/identifier"doi:10.1161/circresaha.110.237867"xsd:string
http://purl.uniprot.org/citations/21372286http://purl.uniprot.org/core/author"Chen H."xsd:string
http://purl.uniprot.org/citations/21372286http://purl.uniprot.org/core/author"Lin S.F."xsd:string
http://purl.uniprot.org/citations/21372286http://purl.uniprot.org/core/author"Zhang W."xsd:string
http://purl.uniprot.org/citations/21372286http://purl.uniprot.org/core/author"Xu X."xsd:string
http://purl.uniprot.org/citations/21372286http://purl.uniprot.org/core/author"Zhu W."xsd:string
http://purl.uniprot.org/citations/21372286http://purl.uniprot.org/core/author"Chen P.S."xsd:string
http://purl.uniprot.org/citations/21372286http://purl.uniprot.org/core/author"Bu G."xsd:string
http://purl.uniprot.org/citations/21372286http://purl.uniprot.org/core/author"Maruyama M."xsd:string
http://purl.uniprot.org/citations/21372286http://purl.uniprot.org/core/author"Yong W."xsd:string
http://purl.uniprot.org/citations/21372286http://purl.uniprot.org/core/author"Guatimosim S."xsd:string
http://purl.uniprot.org/citations/21372286http://purl.uniprot.org/core/author"Lederer W.J."xsd:string
http://purl.uniprot.org/citations/21372286http://purl.uniprot.org/core/author"Shou W."xsd:string
http://purl.uniprot.org/citations/21372286http://purl.uniprot.org/core/author"Song L.S."xsd:string
http://purl.uniprot.org/citations/21372286http://purl.uniprot.org/core/author"Li B.Y."xsd:string
http://purl.uniprot.org/citations/21372286http://purl.uniprot.org/core/author"Field L.J."xsd:string
http://purl.uniprot.org/citations/21372286http://purl.uniprot.org/core/author"Rubart M."xsd:string
http://purl.uniprot.org/citations/21372286http://purl.uniprot.org/core/author"Fishbein M.C."xsd:string
http://purl.uniprot.org/citations/21372286http://purl.uniprot.org/core/author"Schild J.H."xsd:string
http://purl.uniprot.org/citations/21372286http://purl.uniprot.org/core/date"2011"xsd:gYear
http://purl.uniprot.org/citations/21372286http://purl.uniprot.org/core/name"Circ Res"xsd:string
http://purl.uniprot.org/citations/21372286http://purl.uniprot.org/core/pages"1042-1052"xsd:string
http://purl.uniprot.org/citations/21372286http://purl.uniprot.org/core/title"FKBP12 is a critical regulator of the heart rhythm and the cardiac voltage-gated sodium current in mice."xsd:string
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