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EGFR inhibition protects cardiac damage and remodeling through attenuating oxidative stress in STZ-induced diabetic
Dandan Liang1, Peng Zhong2, Jie Hu1
1Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
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.
Insights
Epidermal growth factor receptors (EGFR) play a key role in diabetic heart damage. Inhibiting EGFR reduced oxidative stress and cardiac remodeling in diabetic mice, suggesting EGFR as a potential therapeutic target for diabetic cardiomyopathy.
Area of Science:
- Cardiovascular Research
- Metabolic Diseases
- Molecular Biology
Background:
- Diabetes mellitus is closely linked to cardiomyopathy, but mechanisms remain unclear.
- Epidermal growth factor receptors (EGFR) are implicated in diabetes-induced cardiac injury.
- The specific role of EGFR in the diabetic heart requires further investigation.
Purpose of the Study:
- To elucidate the role of EGFR in the pathogenesis of diabetic heart injury.
- To investigate the therapeutic potential of EGFR inhibitors in diabetic cardiomyopathy.
Main Methods:
- Type 1 diabetic mice induced by streptozotocin were treated with EGFR inhibitors (AG1478, 451).
- In vitro studies used high glucose concentrations on H9C2 cells and primary cardiomyocytes with EGFR inhibitors or sh-RNA.
- Assessed EGFR phosphorylation, AKT, reactive oxygen species (ROS) levels, NADPH oxidase activity, and cardiac remodeling markers.
Main Results:
- Diabetes induced EGFR/AKT phosphorylation, increased cardiac ROS, and led to cardiac remodeling (hypertrophy, apoptosis, fibrosis).
- EGFR inhibitors attenuated these diabetes-induced molecular and pathological changes.
- In vitro, EGFR inhibition/silencing reduced high glucose-induced ROS generation and cardiomyocyte apoptosis, linked to decreased NADPH oxidase activity.
Conclusions:
- EGFR plays a critical role in the pathogenesis of streptozotocin-induced diabetic cardiac damage and remodeling.
- EGFR mediates diabetic cardiac injury via reactive oxygen species generation.
- EGFR inhibition presents a potential therapeutic strategy for treating diabetic cardiomyopathy.
