Neuregulin-erbB Signaling in Myocardial Remodeling

神经调节蛋白是一种生长因子，通过erbB受体酪氨酸激酶家族在不同组织中以旁分泌的方式发挥作用。包括我们自己实验室的大量工作表明，NeuRegin-1(NRG-1)在内皮细胞-心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时心脏结构和功能的改变中发挥作用。我们使用了原代培养的心肌细胞和内皮细胞的体外研究，以了解神经调节蛋白-erb B系统在心肌中的作用。我们发现，重组NRG-1可以激活和失活分离的心肌细胞的生长途径。此外，我们还发现NRG-1可以激活抗凋亡信号以及增加细胞保护性抗氧化酶的表达。我们进一步发现心脏微血管内皮细胞表达NRG-1α，并在几种与心力衰竭发病机制有关的刺激反应中增加NRG-1α的表达。这些观察结果导致了一个总体假设，即成年心肌中的NRG-1-erbB信号通过调节生长和生存信号通路来维持心肌的结构和功能，并在重塑刺激下上调，从而抑制心肌重塑反应。我们将利用心肌细胞和内皮细胞的体外研究以及心肌重构的体内模型，在5个特定的目标上探讨这一假说。总而言之，这项工作将有助于确定NRG-1-erbB信号如何在心肌功能障碍的背景下加剧或调节心肌重构，并最终可能导致终止导致心力衰竭进展的不利心肌重构的新的治疗方法。

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.