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.
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