Dilated cardiomyopathy is associated with reduced expression of the cardiac sodium channel Scn5a

Abstract

OBJECTIVE: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.