Neuregulin-erbB Signaling in Myocardial Remodeling

神经调节蛋白是通过受体酪氨酸激酶的erbB家族以旁分泌方式在不同组织中起作用的生长因子。 包括我们自己实验室的工作在内的大量工作表明，神经调节蛋白-1（NRG-1）在内皮细胞-肌细胞串扰中发挥作用，最近的临床数据表明，该系统可能在心力衰竭中发生的心脏结构和功能的改变中发挥作用。 我们已经在原代培养的心肌细胞和内皮细胞的体外研究，以了解神经调节素-erbB系统在心肌中的作用。 我们已经发现，重组NRG-1可以激活和抑制分离的心肌细胞的生长途径。 此外，我们发现NRG-1可以激活抗凋亡信号，以及增加细胞保护性抗氧化酶在分离的心室肌细胞中的表达。 我们进一步发现，心脏微血管内皮细胞表达NRG-1 α，并增加NRG-1 α的表达，以响应与心力衰竭发病机制有关的几种刺激。 这些观察结果导致了以下总体假设：成年心肌中的NRG-1-erbB信号传导通过调节生长和存活信号传导途径维持心肌结构和功能，并且响应于重塑刺激而上调，从而抑制心肌重塑反应。 我们将在5个特定的目标，使用心肌细胞和内皮细胞的体外研究，并在心肌重塑的体内模型来探讨这一假设。 总的来说，这项工作将有助于确定如何NRG-1-erbB信号加重或调节心肌重塑的心肌功能障碍的设置，并可能最终导致新的治疗方法来中断不良心肌重塑导致心力衰竭的进展。

Neuregulins are growth factors that act in a paracrine manner in diverse tissues through the erbB family of receptor tyrosine kinases. A body of work including that from our own laboratory suggests that neuregulin-1 (NRG-1) plays a role in endothelial cell-myocyte crosstalk, and recent clinical data suggests that this system may play a role in the alterations in cardiac structure and function that occur in heart failure. We have used in vitro studies of cardiac myocytes and endothelial cells in primary culture to understand the role of the neuregulin-erbB system in the myocardium. We have found that a recombinant NRG-1 can both activate and inactivate growth pathways in isolated cardiac cells. Moreover we have found that NRG-1 can activate anti-apoptotic signaling as well as increase the expression of cytoprotective antioxidant enzymes in isolated ventricular mycoytes. We have further found that cardiac microvascular endothelial cells express NRG-1alpha, and increase NRG-1alpha expression in response to several stimuli implicated in the pathogenesis of heart failure. These observations have lead to the overall hypothesis that NRG-1-erbB signaling in the adult myocardium maintains myocardial structure and function through the regulation of growth and survival signaling pathways, and is upregulated in response to remodeling stimuli resulting in a dampening of myocardial remodeling responses. We will approach this hypothesis in 5 specific aims, using in vitro studies of cardiac myocytes and endothelial cells, and in vivo models of myocardial remodeling. Collectively this work will help to determine how NRG-1-erbB signaling exacerbates or modulates myocardial remodeling in the setting of myocardial dysfunction, and may ultimately lead to novel therapeutic approaches to interrupt adverse myocardial remodeling leading to the progression of heart failure.