Transcription Enhancer Factor-1-Related Factor-Transgenic Mice Develop Cardiac Conduction Defects Associated With Altered Connexin Phosphorylation

Hsiao-Huei Chen; Catherine J Baty; Tomoji Maeda; Steven Brooks; Linda C Baker; Takahisa Ueyama; Erdal Gursoy; Samir Saba; Guy Salama; Barry London; Alexandre F.R Stewart

doi:10.1161/01.CIR.0000146902.84099.26

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Transcription Enhancer Factor-1-Related Factor-Transgenic Mice Develop Cardiac Conduction Defects Associated With Altered Connexin Phosphorylation

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Transcription Enhancer Factor-1-Related Factor-Transgenic Mice Develop Cardiac Conduction Defects Associated With Altered Connexin Phosphorylation

Hsiao-Huei Chen, Catherine J Baty, Tomoji Maeda, Steven Brooks, Linda C Baker, Takahisa Ueyama, Erdal Gursoy, Samir Saba, Guy Salama, Barry London, …

Circulation (New York, N.Y.), Vol.110(19), pp.2980-2987

11/09/2004

DOI: 10.1161/01.CIR.0000146902.84099.26

PMID: 15520314

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Abstract

Background: Conduction system defects and slowed ventricular conduction are common in patients with systolic dysfunction and contribute to arrhythmias and sudden death. In animal models of heart failure, cardiac alpha1-adrenergic signaling is constitutively activated. Here, we report the effects of constitutive activation of alpha1-adrenergic signaling on connexin phosphorylation and cardiac conduction. Methods and results: Transgenic mice were generated with cardiac-specific overexpression of the transcription factor RTEF-1 (transcription enhancer factor-1-related factor), which mediates alpha1-adrenergic signaling in cardiac myocytes. Surface and intracardiac ECGs revealed prolongation of the PR, QRS, and AH intervals and the appearance of progressive atrial arrhythmias in RTEF-1 mice. Optical mapping using voltage-sensitive dye revealed slower conduction velocities across the atrial and ventricular myocardium. Intercellular dye transfer between RTEF-1 transgenic cardiac myocytes confirmed impaired conduction at the cellular level. Conduction defects were correlated with dephosphorylation of connexin40 and connexin43 and upregulation of protein phosphatase 1beta (PP1beta). Overexpression of PP1beta in HeLa cells dephosphorylated cardiac connexin. Confocal microscopy revealed increased levels of dephosphorylated connexin43 at the cardiac gap junctions in RTEF-1 mice, suggesting that defective conduction is a result of impaired gap-junction conductance rather than assembly. Conclusions: Constitutive activation of alpha1-adrenergic signaling through the RTEF-1 transcription factor results in chronic elevation of PP1beta expression and connexin dephosphorylation. This mechanism may underlie some defects in cardiac conduction.

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Title: Subtitle: Transcription Enhancer Factor-1-Related Factor-Transgenic Mice Develop Cardiac Conduction Defects Associated With Altered Connexin Phosphorylation
Creators: Hsiao-Huei Chen - From the Cardiovascular Institute (H.-H.C., T.M., S.B., T.U., E.G., S.S., B.L., A.F.R.S.) and the Department of Cell Biology and Physiology (C.J.B., L.C.B., G.S.), University of Pittsburgh, Pittsburgh, Pa
Catherine J Baty - From the Cardiovascular Institute (H.-H.C., T.M., S.B., T.U., E.G., S.S., B.L., A.F.R.S.) and the Department of Cell Biology and Physiology (C.J.B., L.C.B., G.S.), University of Pittsburgh, Pittsburgh, Pa
Tomoji Maeda - From the Cardiovascular Institute (H.-H.C., T.M., S.B., T.U., E.G., S.S., B.L., A.F.R.S.) and the Department of Cell Biology and Physiology (C.J.B., L.C.B., G.S.), University of Pittsburgh, Pittsburgh, Pa
Steven Brooks - From the Cardiovascular Institute (H.-H.C., T.M., S.B., T.U., E.G., S.S., B.L., A.F.R.S.) and the Department of Cell Biology and Physiology (C.J.B., L.C.B., G.S.), University of Pittsburgh, Pittsburgh, Pa
Linda C Baker - From the Cardiovascular Institute (H.-H.C., T.M., S.B., T.U., E.G., S.S., B.L., A.F.R.S.) and the Department of Cell Biology and Physiology (C.J.B., L.C.B., G.S.), University of Pittsburgh, Pittsburgh, Pa
Takahisa Ueyama - From the Cardiovascular Institute (H.-H.C., T.M., S.B., T.U., E.G., S.S., B.L., A.F.R.S.) and the Department of Cell Biology and Physiology (C.J.B., L.C.B., G.S.), University of Pittsburgh, Pittsburgh, Pa
Erdal Gursoy - From the Cardiovascular Institute (H.-H.C., T.M., S.B., T.U., E.G., S.S., B.L., A.F.R.S.) and the Department of Cell Biology and Physiology (C.J.B., L.C.B., G.S.), University of Pittsburgh, Pittsburgh, Pa
Samir Saba - From the Cardiovascular Institute (H.-H.C., T.M., S.B., T.U., E.G., S.S., B.L., A.F.R.S.) and the Department of Cell Biology and Physiology (C.J.B., L.C.B., G.S.), University of Pittsburgh, Pittsburgh, Pa
Guy Salama - From the Cardiovascular Institute (H.-H.C., T.M., S.B., T.U., E.G., S.S., B.L., A.F.R.S.) and the Department of Cell Biology and Physiology (C.J.B., L.C.B., G.S.), University of Pittsburgh, Pittsburgh, Pa
Barry London - From the Cardiovascular Institute (H.-H.C., T.M., S.B., T.U., E.G., S.S., B.L., A.F.R.S.) and the Department of Cell Biology and Physiology (C.J.B., L.C.B., G.S.), University of Pittsburgh, Pittsburgh, Pa
Alexandre F.R Stewart - From the Cardiovascular Institute (H.-H.C., T.M., S.B., T.U., E.G., S.S., B.L., A.F.R.S.) and the Department of Cell Biology and Physiology (C.J.B., L.C.B., G.S.), University of Pittsburgh, Pittsburgh, Pa
Resource Type: Journal article
Publication Details: Circulation (New York, N.Y.), Vol.110(19), pp.2980-2987
DOI: 10.1161/01.CIR.0000146902.84099.26
PMID: 15520314
NLM abbreviation: Circulation
ISSN: 0009-7322
eISSN: 1524-4539
Publisher: Lippincott Williams & Wilkins
Language: English
Date published: 11/09/2004
Academic Unit: Molecular Physiology and Biophysics; Cardiovascular Medicine; Internal Medicine
Record Identifier: 9984025593402771

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