Role of GAB1/PI3K/AKT signaling high glucose-induced cardiomyocyte apoptosis - 08/08/17
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Graphical abstract |
This study analyzed the role and mechanism of GAB1/AKT signaling in HG-induced apoptosis. The down-regulation of GAB1 occurred concurrently with HG-induced cardiomyocytes apoptosis and in the heart tissues of offspring of diabetic rats in vitro and in vivo. Down-regulation of XIAP and increased activities of Caspase3/7 was associated with GAB1-mediated cardiomyocyte apoptosis in response to HG treatment. Further study showed that the phosphorylation levels of AKT (Ser473) decreased after HG treatment. Over-expression of GAB1 resisted the reduction in AKT phosphorylation in response to HG. LY294002, which is an effective inhibitor of the PI3K/AKT signaling pathway, partly inhibited GAB1 to suppress apoptosis induced by HG in cardiomyocytes, and partly suppressed GAB1 to resist the decrease of XIAP in response to HG, indicating AKT signaling, XIAP and Caspase3/7 participated in GAB1-mediated cardiomyocyte apoptosis in response to HG.
Abstract |
Gestational diabetes mellitus (GDM) is a risk factor for abnormal heart development. Previous work showed that a decrease of myocardial cells and an increase of apoptotic cells leading to heart defects under hyperglycemia, and many genes and protein have been found to play important roles in cardiomyocyte apoptosis. However, there are still many blind nodes in HG-induced cardiac apoptosis. Our study showed that down-regulation of GAB1 occurred concurrently with HG-induced cardiomyocytes apoptosis and in the heart tissues of offspring of diabetic rats in vitro and in vivo. MTT and apoptosis assay showed GAB1 played a key role in mediating HG-induced apoptosis of cardiomyocytes. Down-regulation of XIAP and increased activities of Caspase3/7 was associated with GAB1-mediated cardiomyocyte apoptosis in response to HG treatment. Further study showed that the phosphorylation levels of AKT (Ser473) decreased after HG treatment. Over-expression of GAB1 resisted the reduction in AKT phosphorylation in response to HG. LY294002, which is an effective inhibitor of the PI3K/AKT signaling pathway, partly inhibited GAB1 to suppress apoptosis induced by HG in cardiomyocytes, and partly suppressed GAB1 to resist the decrease of XIAP in response to HG, indicating AKT signaling, XIAP, and Caspase3/7 participated in GAB1-mediated cardiomyocyte apoptosis in response to HG. Generally, we demonstrate a novel role of GAB1 and its down-stream signaling PI3K/AKT for modulating cardiomyocyte apoptosis in response to high glucose in vitro and vivo.
Le texte complet de cet article est disponible en PDF.Abbreviations : GDM, CHD, DOS, PI3K, DMEM, GFP, MTT, RT, PVDF, RNAi, siRNA, HG
Keywords : Cardiomyocyte apoptosis, Heart, Maternal diabetes, GAB1, High glucose
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Vol 93
P. 1197-1204 - septembre 2017 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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