Published Online
on November 1, 2004

A more recent version of this article appeared on November 9, 2004

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Submitted on February 9, 2004
Revised on June 9, 2004
Accepted on June 10, 2004

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

Hsiao-Huei Chen PhD, Catherine J. Baty DVM, PhD, Tomoji Maeda PhD, Steven Brooks MD, Linda C. Baker PhD, Takahisa Ueyama MD, PhD, Erdal Gursoy MD, PhD, Samir Saba MD, Guy Salama PhD, Barry London MD, PhD, and Alexandre F.R. Stewart PhD^*

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.

^* To whom correspondence should be addressed. E-mail: stewartaf{at}upmc.edu.

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 ₁-adrenergic signaling is constitutively activated. Here, we report the effects of constitutive activation of ₁-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 ₁-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 1 (PP1). Overexpression of PP1 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.

Conclusion--Constitutive activation of ₁-adrenergic signaling through the RTEF-1 transcription factor results in chronic elevation of PP1 expression and connexin dephosphorylation. This mechanism may underlie some defects in cardiac conduction.

Key words: gap junctions • transcription factors • ventricles • atrium • arrhythmias

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