Hesse Michael, Kondo Colleen S, Clark Robert B, Su Lin, Allen Frances L, Geary-Joo Colleen T M, Kunnathu Stanley, Severson David L, Nygren Anders, Giles Wayne R, Cross James C
Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada.
Cardiovasc Res. 2007 Aug 1;75(3):498-509. doi: 10.1016/j.cardiores.2007.04.009. Epub 2007 Apr 21.
Dilated cardiomyopathy (DCM) leads to dilation of the cardiac chambers and congestive heart failure. Recent reports have associated mutations in the SCN5A gene, which codes for the major cardiac sodium channel Nav1.5, with DCM. Although DCM is the most common form of cardiomyopathy, no animal studies have established this functional connection.
We have produced transgenic mice that ectopically express the transcriptional repressor Snail in heart. These animals display severe DCM, ECG abnormalities, conduction defects, revealed by voltage-sensitive dye imaging, and significantly reduced voltage-gated sodium current as measured by patch clamping. There is a concomitant decrease in expression of the major cardiac sodium channel gene Scn5a, which we show by gene reporter assays and electrophoretic mobility shift assays is a direct target of Snail.
Our findings indicate that a decrease in Scn5a expression and significant reduction in sodium current can result in DCM, and support the hypothesis that some mutations in the human SCN5A gene can lead to DCM.
扩张型心肌病（DCM）会导致心腔扩张和充血性心力衰竭。最近的报告表明，编码主要心脏钠通道Nav1.5的SCN5A基因突变与DCM有关。尽管DCM是最常见的心肌病形式，但尚无动物研究证实这种功能联系。
我们制备了在心脏中异位表达转录抑制因子Snail的转基因小鼠。这些动物表现出严重的DCM、心电图异常、传导缺陷（通过电压敏感染料成像显示）以及通过膜片钳测量的电压门控钠电流显著降低。主要心脏钠通道基因Scn5a的表达随之减少，我们通过基因报告分析和电泳迁移率变动分析表明，Scn5a是Snail的直接靶点。
我们的研究结果表明，Scn5a表达降低和钠电流显著减少可导致DCM，并支持以下假设：人类SCN5A基因的某些突变可导致DCM。
