Human heart failure (HF) has been associated with reduced cardiac sodium channel current. Recently, we have shown that downregulation of cardiac Na+ channels (SCN5A) can contribute to arrhythmic risk and that upregulation can mitigate that risk. Furthermore, we have shown that the reduction in cardiac SCN5A mRNA abundance is reflected in circulating white blood cells (WBCs), which also express SCN5A, and that a reduction in SCN5A is highly predictive of appropriate implanted cardiac defibrillator (ICD) therapy. These data suggest that SCN5A regulation is critical to arrhythmic risk in HF. In part, the reduction in SCN5A is mediated by abnormal mRNA splicing. In this application, we intend to explore an entirely novel mechanism by which SCN5A mRNA abundance is reduced in HF. In preliminary data, we show that HuR, a member of a class of RNA stabilizing proteins that bind to AU-rich elements, 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 Na+ channel and increased arrhythmic risk seen in HF. Hypothesis: We propose that HuR is downregulated in HF, that this downregulation contributes to reduced Na+ current and increased arrhythmic risk, and that upregulation of HuR will reduce Na+ channel downregulation and arrhythmic risk in HF.
Aim 1 : Determine the extent to which HuR can regulate Na+ currents in cardiomyocytes.
Aim 2 : Determine the mechanism and extent to which HuR activity is downregulated in ischemic and nonischemic cardiomyopathy and the correlation with Na+ channel mRNA, protein, and current.
Aim 3 : Determine the extent to which overexpression of HuR can raise Na+ channel mRNA, raise Na+ channel current, and reduce arrhythmic risk in ischemic and nonischemic cardiomyopathy.
The cause of sudden death in heart failure is unknown. This application will explore one potential cause, abnormal sodium channel processing, establishing the mechanism and possible elucidating prevention strategies. Moreover, if white cells show similar abnormalities, this work may lead to a blood test to predict sudden death risk in heart failure.
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