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

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.

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  • Authors+Show Affiliations

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    Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.

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    Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Department of Cardiology, The 5th Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China.

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    Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.

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    Department of Gynaecology, The 1st Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.

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    Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.

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    Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.

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    Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.

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    Department of Cardiology, The 5th Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China.

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    Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.

    Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: wzmcliangguang@163.com.

    Source

    MeSH

    Animals
    Apoptosis
    Blood Glucose
    Body Weight
    Cell Line
    Diabetes Mellitus, Experimental
    Diabetic Cardiomyopathies
    Disease Models, Animal
    ErbB Receptors
    Fibrosis
    Male
    Mice
    Myocardium
    Oxidative Stress
    Proto-Oncogene Proteins c-akt
    Quinazolines
    Reactive Oxygen Species
    Signal Transduction
    Tyrphostins
    Ventricular Remodeling

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    25758431

    Citation

    Liang, Dandan, et al. "EGFR Inhibition Protects Cardiac Damage and Remodeling Through Attenuating Oxidative Stress in STZ-induced Diabetic Mouse Model." Journal of Molecular and Cellular Cardiology, vol. 82, 2015, pp. 63-74.
    Liang D, Zhong P, Hu J, et al. EGFR inhibition protects cardiac damage and remodeling through attenuating oxidative stress in STZ-induced diabetic mouse model. J Mol Cell Cardiol. 2015;82:63-74.
    Liang, D., Zhong, P., Hu, J., Lin, F., Qian, Y., Xu, Z., ... Liang, G. (2015). EGFR inhibition protects cardiac damage and remodeling through attenuating oxidative stress in STZ-induced diabetic mouse model. Journal of Molecular and Cellular Cardiology, 82, pp. 63-74. doi:10.1016/j.yjmcc.2015.02.029.
    Liang D, et al. EGFR Inhibition Protects Cardiac Damage and Remodeling Through Attenuating Oxidative Stress in STZ-induced Diabetic Mouse Model. J Mol Cell Cardiol. 2015;82:63-74. PubMed PMID: 25758431.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - EGFR inhibition protects cardiac damage and remodeling through attenuating oxidative stress in STZ-induced diabetic mouse model. AU - Liang,Dandan, AU - Zhong,Peng, AU - Hu,Jie, AU - Lin,Feng, AU - Qian,Yuanyuan, AU - Xu,Zheng, AU - Wang,Jingying, AU - Zeng,Chunlai, AU - Li,Xiaokun, AU - Liang,Guang, Y1 - 2015/03/07/ PY - 2014/11/25/received PY - 2015/02/14/revised PY - 2015/02/27/accepted PY - 2015/3/12/entrez PY - 2015/3/12/pubmed PY - 2016/1/7/medline KW - Diabetic cardiomyopathy KW - EGFR inhibitor KW - Epidermal growth factor receptor KW - Oxidative stress KW - ROS SP - 63 EP - 74 JF - Journal of molecular and cellular cardiology JO - J. Mol. Cell. Cardiol. VL - 82 N2 - 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. SN - 1095-8584 UR - https://www.unboundmedicine.com/medline/citation/25758431/EGFR_inhibition_protects_cardiac_damage_and_remodeling_through_attenuating_oxidative_stress_in_STZ_induced_diabetic_mouse_model_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-2828(15)00074-7 DB - PRIME DP - Unbound Medicine ER -