EGFR inhibition protects the cardiac remodeling through attenuating oxidative stress in STZ‐induced diabetic mouse model

Background Diabetes mellitus is strongly associated with cardiomyopathy. The underlying mechanisms for the development of diabetic cardiomyopathy are complex and not totally resolved. Recent studies showed epidermal growth factor receptor(EGFR) has been involved in the diabetes-induced cardiac injury. However, there exists a paradox of the role of EGFR in diabetic heart. The aim of the present study is to further determine the role of EGRF in the pathogenesis of diabetic cardiomyopathy. Methods: C57BL/6J mice were injected with streptozotocin only or in combination with EGFR inhibitors (AG1478 and a new inhibitor 451) for 8 weeks. In vitro, cardiac H9C2 cells were treated by high glucose concentration (HGC) in the presence or absence of ERFR inhibitors. Results: In type 1 diabetes model, diabetes induced phospohorylation of EGFR and AKT, increased cardiac ROS level, and ultimately leaded to cardiac remodeling including cardiac hypertrophy, disorganization, apoptosis and fibrosis. Interestingly, all these molecular and pathological alterations were attenuated by the treatment with EGFR inhibitors. In vitro, similar results were also observed in cardiac cells exposed to HGC. In addition, the HGC-induced cardiomyocyte injuries were also significantly reduced by NAC, an inhibitor of ROS. Conclusion: This study further provides evidence for a detrimental role of EGFR in the pathogenesis of diabetic cardiomyopathy via activating ROS generation, and suggests that EGFR may be a potencial therapeutic target in treating diabetic cardiomyopathy.