Copyright © 2006, European Society of Cardiology
Inhibition of basic leucine zipper transcription is a major mediator of atrial dilatation
aDepartment of Internal Medicine C and Cardiology, Rambam Medical Center, Haifa, Israel
bDepartment of Molecular Genetics, The B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, 7 Efron St., Bat-Galim, Haifa 31096, Israel
cDepartment of Pathology, Rambam Medical Center, Israel
dPhilips Institute of Oral and Craniofacial Molecular Biology, Richmond, VA, USA
eOral and Pharyngeal Cancer Branch, National Institute of Dental Research, National Institute of Health, Bethesda, MD, USA
* Corresponding author. Tel.: +972 4 8295226; fax: +972 4 8295225. Email address: aronheim{at}tx.technion.ac.il
Objective Atrial fibrillation is the most prevalent clinically significant cardiac arrhythmia. Atrial dilatation, a predictor of atrial fibrillation, is thought to result from increased ventricular pressure. However, the underlying molecular mechanisms responsible for atrial dilatation are largely unknown. Here we sought to examine whether the expression of a basic leucine zipper inhibitor protein, JDP2, in the heart is sufficient for the generation of atrial dilatation.
Methods A tetracycline-regulated transgene was used to express JDP2 specifically in the mouse heart. Mice hearts were dissected and subjected to Northern and Western analysis, or analyzed by ECG recording and echocardiography. Regulation of gene expression was studied using electromobility shift assays and luciferase gene reporter analysis.
Results Expression of JDP2 resulted in massive bi-atrial dilatation, defects in conduction, and a lethal phenotype. These effects were developmentally independent, acquired during adulthood, and were reversible upon abolishing of JDP2 expression. Connexin 40 and myosin light chain 2a expression were identified as potential target genes.
Conclusion Expression of basic leucine zipper transcription inhibitors is sufficient to results in atrial dilatation. This dilatation is acquired postnatally and is reversible. Thus, basic leucine zipper transcription inhibitors may be a relevant therapeutic target for preventing atrial dilatation and atrial fibrillation.
KEYWORDS Trial function; Hypertrophy; Connexins; Gene expression
Time for primary review 33 days
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