Abstract 15892: mRNA Stability Hu Proteins Regulate Human Cardiac Sodium Channel Expression

Abstract

Human heart failure has been associated with reduced cardiac Nav1.5 Na+ channel current and SCN5A mRNA abundance. We hypothesized that reduced mRNA stability would contribute to the reduction of SCN5A mRNA. Hu proteins are known to contribute to mRNA stability The SCN5A mRNA 3’-untranslated region (UTR) contains two sets of putative Hu protein binding site. Over-expression of HuR and HuB in cardiomyocytes derived from primary human fetal ventricle increased wild-type SCN5A mRNA 46.3% (P=0.004) and 60.7% (P=0.008), respectively. Knocking down of HuR or HuB by siRNA decreased SCN5A mRNA by 27.5% (P=0.000) and 20.4% (P=0.02). RNA immunoprecipitation showed HuR associated with SCN5A mRNA. This suggested Hu family proteins might play an important role in upregulation of SCN5A expression by stabilizing SCN5A mRNA. In addition, we found HuR mRNA decreased 38.9% (P=0.034) in peripheral white blood cells of heart failure patients with implanted cardioverter-defibrillator (ICD) and evidence of appropriate event-driven therapy compared to control subjects. The decrease of HuR mRNA correlated with a reduction of wild-type SCN5A mRNA abundance in white blood cells from these patients. Our results demonstrate an additional layer of SCN5A posttranscriptional regulation in addition to alternative splicing that can contribute to sodium channel down-regulation in heart failure. Our results also suggest that circulating HU protein assessment may be useful in arrhythmic risk stratification and that exogenous HU protein overexpression may help reduce arrhythmic risk in heart failure.