title: Grb2-associated binder 1 is essential for cardioprotection against ischemia/reperfusion injury.
abstract: 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.
authors.affiliation: Laboratory of Vascular Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, 100871, China.
authors.forename: Lulu
authors.initials: L
authors.lastname: Sun
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
authors.forename: Beibei
authors.initials: B
authors.lastname: Jiang
authors.forename: Yanli
authors.initials: Y
authors.lastname: Li
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Deng
authors.forename: Min
authors.initials: M
authors.lastname: Sun
authors.forename: Xiangbo
authors.initials: X
authors.lastname: An
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.forename: Rongli
authors.initials: R
authors.lastname: Zhang
authors.forename: Yao
authors.initials: Y
authors.lastname: Lu
authors.forename: De-Sheng
authors.initials: DS
authors.lastname: Zhu
authors.forename: Yingqing
authors.initials: Y
authors.lastname: Huo
authors.forename: Gen-Sheng
authors.initials: GS
authors.lastname: Feng
authors.forename: Youyi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jincai
authors.initials: J
authors.lastname: Luo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D016277:Ventricular Function, Left; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C490897:Gab1 protein, mouse; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3