EGFR inhibition protects cardiac damage and remodeling through attenuating oxidative stress in STZ-induced diabetic mouse model. (May 2015)

• Record Type: Journal Article
• Authors: Liang, Dandan; Zhong, Peng; Hu, Jie; Lin, Feng; Qian, Yuanyuan; Xu, Zheng; Wang, Jingying; Zeng, Chunlai; Li, Xiaokun; Liang, Guang
• Is Part Of: Journal of molecular and cellular cardiology. Volume 82(2015:May)
• Page Start: 63
• Page End: 74
• Publication Date: 2015-05
• Subjects: Epidermal growth factor receptor -- Diabetic cardiomyopathy -- Oxidative stress -- ROS -- EGFR inhibitor; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2015.02.029
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Diabetes mellitus is strongly associated with cardiomyopathy. The underlying mechanisms for the development of diabetic cardiomyopathy are complex and not completely understood. Recent studies showed that epidermal growth factor receptors (EGFRs) are involved in diabetes-induced cardiac injury. However, the role of EGFR in the diabetic heart has yet to be confirmed. The aim of the present study is to further determine the role of EGRF in the pathogenesis of diabetic heart injury. The type 1 diabetic mice induced by streptozotocin were treated with EGFR inhibitors (AG1478 and 451) for 8 weeks, respectively. It was observed that diabetes induced phospohorylation of EGFR and AKT, increased cardiac ROS levels, and ultimately led to cardiac remodeling including cardiac hypertrophy, disorganization, apoptosis, and fibrosis, while all these molecular and pathological alterations were attenuated by the treatment with EGFR inhibitors. In vitro, either pharmacological inhibition of EGFR/AKT or sh-RNA silencing of EGFR significantly inhibited high concentration glucose (HG)-induced ROS generation and subsequently cell apoptosis in both cardiac H9C2 cells and primary rat cardiomyocytes, respectively. The ROS reduction by EGFR inhibitor was associated with the decreased NADPH oxidase activity and expression in H9c2 cells. HG-induced cardiomyocyte injuries were also reduced by NAC, an inhibitor of ROS. This study provides evidence that EGFR has a key role in the pathogenesis of STZ-induced diabetic cardiac damage and remodeling via ROS generation, and suggests that EGFR may be a potential target in treating diabetic cardiomyopathy. Highlights: Epidermal growth factor receptor (EGFR) plays a vital role in STZ-induced diabetic cardiac injury. EGFR inhibition attenuates hyperglycemia/high glucose-induced cardiac injury via reducing NOX activity and ROS generation. ROS production mediates the regulation of EGFR in diabetic heart injury. EGFR may be a potential target in treating diabetic cardiomyopathy.