CARDIAC NA-CA EXCHANGER: HYPERTROPHIC REGULATION

晚期肥厚和心力衰竭的病因极其复杂，但细胞钙调节改变似乎是心律失常和收缩功能障碍的最终共同原因。肌浆网钙-三磷酸腺苷酶(SERCA)和肌膜Na+-钙交换器(NCX1)是松弛过程中负责将[Ca~(2+)]i降低到低静息水平的两个主要转运体。SERCA的表达和活性在肥厚和衰竭时降低，我们和其他人发现在这种情况下NCX1的表达和活性增加。最近的报道表明，交换器的上调似乎是收缩功能障碍和心律失常发生之间的关键联系。更多的研究证明，通过NCX1抑制钙内流在缺血/再灌流、洋地黄毒性和心房颤动导致的心房折射率缩短中所产生的心脏保护作用。到目前为止，这些结果完全基于急性研究，没有涉及长期治疗。我们发现，Kb-R7943或通过降低[Ca~(2+)]o抑制NCX1钙内流途径(反向模式)，导致信号的激活 导致交换器基因特异性上调的因素。这一新颖而令人兴奋的发现应该会对潜在的长期治疗产生深远的影响，并将交易所活动的监管置于一个全新的视角。该交换器的活性对[Ca~(2+)]_o、[Ca~(2+)]_i、[Na~+]_i和膜电位(Em)非常敏感，也可作为细胞变阻器，参与特定信号转导通路的调节。我们的假设是，交换器活性的改变可以直接激活信号转导通路，从而导致交换器基因表达的变化。这将通过以下目的来检验：1)确定KBrR诱导的p38的激活和NCX1的上调是由交换器直接介导的。2)确定交换器活性的变化是通过直接相互作用还是通过[Ca~(2+)]的变化来转导信号通路的激活。i)确定直接与交换器相互作用的调节p38激活的因素。4)确定介导p38激活的信号通路中的下游因素。这项工作将使 我们更好地了解交换活性在失败中所起的作用，并为治疗开发提供框架。

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.