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

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

Chinese medical journal 2020 Dec 08

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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. 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. 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. Loss of GAB1 promotes VEC autophagy which is associated with ASO. GAB1 and its downstream signaling might be potential therapeutic targets for ASO treatment. Copyright © 2020 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.

Citation

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. Loss of GRB2 associated binding protein 1 in arteriosclerosis obliterans promotes host autophagy. Chinese medical journal. 2020 Dec 08;134(1):73-80