Arrhythmias are the leading cause of death among patients with heart failure (HF), yet their molecular causes are poorly understood. It has been proposed that an increase in the duration of the action potential (AP) of cardiac myocytes is the major arrhythmogenic event during HF. This prolongation of the AP of failing cardiac myocytes occurs in the absence of known genetic changes that affect membrane currents. Preliminary experiments performed in our laboratory suggest that Na+ (INa) and transient outward K+ (Ito) currents are altered during HF in ways that could prolong the AP of failing cardiac myocytes. Our most recent data suggest that a defect in the post-translational processing of Na+ and Kv4 channels during HF is the cause for these dysfunctional INa and Ito currents. Furthermore, we have evidence that links these changes in Na+ and Kv4 channel currents to the activation of the calcineurin/NFAT genetic pathway in the early stages of HF. The overall goal of this application is to test the hypothesis that the changes in INa and Ito currents observed during HF are the result of poor or incomplete glycosylation of these proteins during post-translational processing, due to the activation of NFAT by calcineurin. To test this hypothesis we will perform a series of complementary experiments that involve the use of molecular, cellular, biochemical, electrophysiological and imaging techniques. This proposal has four specific aims. 1) To investigate the effects of a sustained increase in resting Ca2+ levels on INa and Ito in ventricular myocytes. 2) To investigate the effects of calcineurin-induced NFAT activation on INa and Ito. 3) To investigate the molecular determinants of the changes in INa and Ito during HF. 4) To investigate the effects of calcineurin-induced NFAT activation on INa and Ito in a heterologous expression system. The proposed work should provide fundamental information on the molecular mechanisms underlying arrhythmias during HF and could provide insights in the development of effective therapeutic strategies for this condition.
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