Inhibition of basic leucine zipper transcription is a major mediator of atrial dilatation.
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.


CONCLUSIONS
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.
Kehat
Izhak
I
Department of Internal Medicine C and Cardiology, Rambam Medical Center, Haifa, Israel.
Heinrich
Ronit
R
Ben-Izhak
Ofer
O
Miyazaki
Hiroshi
H
Gutkind
J Silvio
JS
Aronheim
Ami
A
D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D016757:Death, Sudden, Cardiac; D004452:Echocardiography; D004562:Electrocardiography; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D016350:Leucine Zippers; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic
D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; C491386:Jundp2 protein, mouse; D012097:Repressor Proteins; D004247:DNA