cardiac-specific over-expression of epidermal growth factor receptor 2 (erbb2) induces pro-survival pathways and hypertrophic cardiomyopathy in mice心脏表达表皮生长因子受体2(erbb2)诱发pro-survival途径和肥厚性心肌病小鼠.pdfVIP

Cardiac-Specific Over-Expression of Epidermal Growth Factor Receptor 2 (ErbB2) Induces Pro-Survival Pathways and Hypertrophic Cardiomyopathy in Mice 1. 1. 1 1 1 1 1 Polina Sysa-Shah , Yi Xu , Xin Guo , Frances Belmonte , Byunghak Kang , Djahida Bedja , Scott Pin , 1,2 1 Noriko Tsuchiya , Kathleen Gabrielson * 1Johns Hopkins University, School of Medicine, Department of Molecular and Comparative Pathobiology, Baltimore, Maryland, United States of America, 2 Drug Safety Evaluation, Drug Developmental Research Laboratories, Shionogi Co., Ltd., Osaka, Japan Abstract Background: Emerging evidence shows that ErbB2 signaling has a critical role in cardiomyocyte physiology, based mainly on findings that blocking ErbB2 for cancer therapy is toxic to cardiac cells. However, consequences of high levels of ErbB2 activity in the heart have not been previously explored. Methodology/Principal Findings: We investigated consequences of cardiac-restricted over-expression of ErbB2 in two novel lines of transgenic mice. Both lines develop striking concentric cardiac hypertrophy, without heart failure or decreased life span. ErbB2 transgenic mice display electrocardiographic characteristics similar to those found in patients with Hypertrophic Cardiomyopathy, with susceptibility to adrenergic-induced arrhythmias. The hypertrophic hearts, which are 2– 3 times larger than those of control littermates, express increased atrial natriuretic peptide and b-myosin heavy chain mRNA, consistent with a hypertrophic phenotype. Cardiomyocytes in these hearts are significantly larger than wild type cardiomyocytes, with enla