Grb2-associated binder 1 is essential for cardioprotection against ischemia/reperfusion injury
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  • 作者:Lulu Sun (1)
    Chao Chen (2)
    Beibei Jiang (1)
    Yanli Li (1)
    Qiuping Deng (1)
    Min Sun (2)
    Xiangbo An (2)
    Xiao Yang (3)
    Ying Yang (1)
    Rongli Zhang (1)
    Yao Lu (1)
    De-Sheng Zhu (4)
    Yingqing Huo (1)
    Gen-Sheng Feng (5)
    Youyi Zhang (2) (6)
    Jincai Luo (1)

    1. Laboratory of Vascular Biology
    ; Institute of Molecular Medicine ; Beijing Key Laboratory of Cardiometabolic Molecular Medicine ; Peking University ; Beijing ; 100871 ; China
    2. Third Hospital
    ; Peking University and Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides Ministry of Health ; Beijing ; China
    3. State Key Laboratory of Proteomics
    ; Institute of Biotechnology and Genetic Laboratory of Development and Disease ; Beijing ; China
    4. Animal Center
    ; Peking University ; Beijing ; China
    5. Department of Pathology
    ; School of Medicine ; University of California ; San Diego ; CA ; 92093-0864 ; USA
    6. Institute of Vascular Medicine
    ; Peking University Third Hospital ; 49 Huayuan-Bei Rd ; Beijing ; 100191 ; China
  • 关键词:Gab1 ; Ischemia/reperfusion injury ; Cardioprotection ; Cell survival
  • 刊名:Basic Research in Cardiology
  • 出版年:2014
  • 出版时间:July 2014
  • 年:2014
  • 卷:109
  • 期:4
  • 全文大小:3,462 KB
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  • 刊物类别:Medicine
  • 刊物主题:Medicine & Public Health
    Cardiology
  • 出版者:Springer Berlin / Heidelberg
  • ISSN:1435-1803
文摘
We have shown recently that endothelial Grb-2-associated binder 1 (Gab1), an intracellular scaffolding adaptor, has a protective effect against limb ischemia via mediating angiogenic signaling pathways. However, the role of Gab1 in cardiac ischemia/reperfusion (I/R) injury remains unknown. In this study, we show that Gab1 is required for cardioprotection against I/R injury. I/R injury led to remarkable phosphorylation of Gab1 in cardiomyocytes. Compared with controls, the mice with cardiomyocyte-specific deletion of Gab1 gene (CGKO mice) exhibited an increase in infarct size and a decrease in cardiac function after I/R injury. Consistently, in hearts of CGKO mice subjected to I/R, the activation of caspase 3 and myocardial apoptosis was markedly enhanced whereas the activation of protein kinase B (Akt) and mitogen-activated protein kinase (MAPK), which are critical for cardiomyocyte survival, was attenuated. Oxidative stress is regarded as a major contributor to myocardial I/R injury. To examine the role of Gab1 in oxidative stress directly, isolated adult cardiomyocytes were subject to oxidant hydrogen peroxide and the cardioprotective effects of Gab1 were confirmed. Furthermore, we found that the phosphorylation of Gab1 and Gab1-mediated activation of Akt and MAPK by oxidative stress was suppressed by ErbB receptor and Src kinase inhibitors, accompanied by an increase in apoptotic cell death. In conclusion, our results suggest that Gab1 is essential for cardioprotection against I/R oxidative injury via mediating survival signaling.

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