Na+ Channel mRNA Regulation in Heart Failure

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Altered gene expression has been traditionally focused on transcriptional regulation. Nevertheless, recent large-scale analyses have revealed that as many as half of all changes in the amounts of mRNA in responses to cellular signals can be attributed to altered rates of mRNA decay. In preliminary d...

Altered gene expression has been traditionally focused on transcriptional regulation. Nevertheless, recent large-scale analyses have revealed that as many as half of all changes in the amounts of mRNA in responses to cellular signals can be attributed to altered rates of mRNA decay. In preliminary data, we show that HuR, a member of a class of RNA stabilizing proteins that bind to AU-rich elements (ARE), is expressed in the heart and contributes to Na+ channel mRNA stability by binding to SCN5A transcript. Furthermore, HuR appears to be downregulated in human HF, perhaps contributing to the downregulation of ion channels and increased arrhythmic risk seen in HF. We propose that HuR is downregulated in HF, that this downregulation contributes to reduced Na+ and other currents and increased arrhythmic risk, and that upregulation of HuR will reduce ion channel downregulations and arrhythmic risk in HF. The investigators specific aims are: Aim 1: Determine the extent to which HuR can regulate ion currents in cardiomyocytes. Aim 2: Determine the relative contributions of known ion channel posttranscriptional control mechanisms. Aim 3: Determine the mechanism and extent to which HuR activity is downregulated in ischemic and nonischemic cardiomyopathy and the correlation with ion channel mRNA, protein, and current. Aim 4: Determine the extent to which overexpression of HuR can raise ion channel mRNA, raise ion channel current, and reduce arrhythmic risk in ischemic and nonischemic cardiomyopathy. Please be notified that only Aim 2 involves the usage of de-identified human heart samples.

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