Loss of GRB2 associated binding protein 1 in arteriosclerosis obliterans promotes host autophagy  

作　　者：Meng Ye Xiang-Jiang Guo Ke-Jia Kan Qi-Hong Ni Jia-Quan Chen Han Wang Xin Qian Guan-Hua Xue Hao-Yu Deng Lan Zhang 

机构地区：[1]Department of Vascular Surgery,RenJi Hospital,School of Medicine,Shanghai Jiaotong University,Shanghai 200127,China

出　　处：《Chinese Medical Journal》2021年第1期73-80,共8页中华医学杂志（英文版）

基　　金：supported by the grants from the Shanghai Municipal Science and Technology Commission(No.14430721400);National Natural Science Foundation(Nos.81700421 and 81670442);Clinical innovative research funding of Shanghai Jiaotong University School of Medicine(No.PY2018-IIC-05)。

摘　　要：Background:Arteriosclerosis obliterans(ASO)is a major cause of adult limb loss worldwide.Autophagy of vascular endothelial cell(VEC)contributes to the ASO progression.However,the molecular mechanism that controls VEC autophagy remains unclear.In this study,we aimed to explore the role of the GRB2 associated binding protein 1(GAB1)in regulating VEC autophagy.Methods:In vivo and in vitro studies were applied to determine the loss of adapt protein GAB1 in association with ASO progression.Histological GAB1 expression was measured in sclerotic vascular intima and normal vascular intima.Gain-and loss-of-function of GAB1 were applied in VEC to determine the effect and potential downstream signaling of GAB1.Results:The autophagy repressor p62 was significantly downregulated in ASO intima as compared to that in healthy donor(0.80 vs.0.20,t=6.43,P<0.05).The expression level of GAB1 mRNA(1.00 vs.0.24,t=7.41,P<0.05)and protein(0.72 vs.0.21,t=5.97,P<0.05)was significantly decreased in ASO group as compared with the control group.Loss of GAB1 led to a remarkable decrease in LC3II(1.19 vs.0.68,t=5.99,P<0.05),whereas overexpression of GAB1 significantly led to a decrease in LC3II level(0.41 vs.0.93,t=7.12,P<0.05).Phosphorylation levels of JNK and p38 were significantly associated with gain-and loss-of-function of GAB1 protein.Conclusion:Loss of GAB1 promotes VEC autophagy which is associated with ASO.GAB1 and its downstream signaling might be potential therapeutic targets for ASO treatment.

关 键 词：Arteriosclerosis obliterans AUTOPHAGY GRB2 associated binding protein 1 JNK pathway p38 kinase pathway 

分 类 号：R543.5[医药卫生—心血管疾病]