Kehat Izhak, Heinrich Ronit, Ben-Izhak Ofer, Miyazaki Hiroshi, Gutkind J Silvio, Aronheim Ami
Department of Internal Medicine C and Cardiology, Rambam Medical Center, Haifa, Israel.
Cardiovasc Res. 2006 Jun 1;70(3):543-54. doi: 10.1016/j.cardiores.2006.02.018. Epub 2006 Mar 6.
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.
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.
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.
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.
心房颤动是临床上最常见的具有重要意义的心律失常。心房扩张是心房颤动的一个预测指标，被认为是心室压力增加所致。然而，导致心房扩张的潜在分子机制在很大程度上尚不清楚。在此，我们试图研究心脏中一种碱性亮氨酸拉链抑制蛋白JDP2的表达是否足以导致心房扩张。
使用四环素调控的转基因在小鼠心脏中特异性表达JDP2。解剖小鼠心脏并进行Northern和Western分析，或通过心电图记录和超声心动图进行分析。使用电泳迁移率变动分析和荧光素酶基因报告分析研究基因表达的调控。
JDP2的表达导致双心房大量扩张、传导缺陷和致死表型。这些效应在发育上是独立的，在成年期获得，并且在JDP2表达被消除后是可逆的。连接蛋白40和肌球蛋白轻链2a的表达被确定为潜在的靶基因。
碱性亮氨酸拉链转录抑制因子的表达足以导致心房扩张。这种扩张是在出生后获得的，并且是可逆的。因此，碱性亮氨酸拉链转录抑制因子可能是预防心房扩张和心房颤动的一个相关治疗靶点。
