The etiologies of late hypertrophy and heart failure are extremely complex but altered cellular calcium regulation appears to be a final common cause in both arrhythmogenesis and contractile dysfunction. The SR Ca2+-ATPase (SERCA) and sarcolemmal Na+-Ca2+ exchanger (NCX1) are two major transporters responsible for reducing [Ca2+]i to a low resting level during relaxation. SERCA expression and activity are decreased in hypertrophy and failure and we and others have shown that expression and activity in NCX1 is increased in this situation. Recent reports have demonstrated that upregulation of the exchanger appears to be a critical link between contractile dysfunction and arrhythmogenesis. Additional studies have documented the cardio-protective effect resulting from inhibition of calcium influx via NCX1 in ischemia/reperfusion, digitalis toxicity and atrial fibrillation-induced shortening of atrial refractiveness. So far these results are solely based on acute studies and do not address long-term treatment. We discovered that inhibition of NCX1 calcium influx pathway (reverse mode) either by KB-R7943 or by lowering [Ca2+]o, resulted in the activation of signaling factors that leads to specific upregulation of the exchanger gene. This novel and exciting finding should have a profound impact on potential long-term treatment and places regulation of exchanger activity in a whole new light. The exchanger, whose activity is acutely sensitive to [Ca2+]o, [Ca2+]i, [Na+]i, and membrane potential (Em), may also act as a cellular rheostat that plays a role in the modulation of specific signal transduction pathways. Our hypothesis is that alteration of exchanger activity can directly activate signal transduction pathways resulting in changes in exchanger gene expression. This will be tested through the following aims: 1) Determine that the KBR induced activation of p38 and upregulation of NCX1 is directly mediated by the exchanger. 2) Determine whether changes in exchanger activity transduce the activation of signaling pathways by direct interaction or via changes in [Ca2+]i. 3) Identify factors interacting directly with the exchanger that mediate the activation of p38. 4) Identify the downstream factors in the signaling pathway mediating p38 activation. This work will allow us to better understand the role that exchanger activity plays in failure and provide a framework for therapeutic development.
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