抄録
EGF family-ErbB receptor signaling plays crucial roles in heart development and preservation of adult cardiac function. Among the ligands for ErbB family receptors, neuregulin-1 (NRG-1) and heparin-binding EGF-like growth factor (HB-EGF) have been shown to be important for cardiac development. We have found that NRG-1 is a critical ligand for ErbB receptors on cardiomyocytes, whereas HB-EGF is for those on cardiac fibroblasts. In addition, the Grb2-associated binder (Gab) family proteins are remarkably phosphorylated upon NRG-1 stimulation in cardiomyocytes. To investigate the function of Gab family proteins, we depleted both Gab1 and Gab2 from the myocardium by crossing conventional Gab2 KO mice and conditional Gab1 KO mice (α-MHC-Cre mice crossed with Gab1flox/flox). Double KO mice of Gab1 and Gab2 (DKO) exhibited cardiomyopathic features (reduced contractility and remarkable ventricular dilation ) with endocardial fibrosis, as demonstrated by echocardiography and histological analyses. Furthermore, the number of capillaries was decreased in the heart. Microarray analysis using DKO mice showed the lack of gene expression of Angiopoietin-1 (Ang1) in response to NRG-1. This lack of Ang1 release might account for endocardial fibrosis and decreased capillary number, because Ang1 is an endothelium-trophic factor. NRG-1 is released from endothelium of capillary and/or endocardium. Thus, Gab family proteins in the myocardium are essential not only for the maintenance of myocardium but also for the stabilization of capillary/endocardial endothelium in the postnatal heart. [J Physiol Sci. 2008;58 Suppl:S44]
