ABSTRACT
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.
Subject(s)
Adult , Humans , Adaptor Proteins, Signal Transducing , Arteriosclerosis Obliterans/genetics , Autophagy , GRB2 Adaptor Protein , Phosphoproteins/metabolism , Phosphorylation , Protein Binding , Signal TransductionABSTRACT
Objective · To investigate the feasibility of four-dimensional flow MRI (4D flow MRI) in evaluating the hemodynamics of forearm autologous arteriovenous fistula (AVF) in renal dialysis patients. Methods · Forty-five patients from Renal Division of Renji Hospital, Shanghai Jiao Tong University School of Medicine were included. Patients with forearm AVF underwent ultrasonography and MRI. The consistency of 4D flow MRI hemodynamic parameters measured by two radiologists and hemodynamic parameters at the same plane of AVF by 4D flow MRI and ultrasonography were analyzed by paired t test. The morphological parameters of AVF were acquired from black blood sequence, and they were used for Pearson correlation analysis with the hemodynamic parameters obtained from 4D flow MRI. Results · Forty-two patients completed the forearm AVF ultrasonography and MRI successfully.Paired t test showed that the consistency of 4D flow MRI hemodynamic parameters by two radiologists was good (all P=0.000), and all hemodynamic parameters measured by 4D flow MRI and ultrasonography were in good agreement (r=0.292-0.569, all P＜0.05) except for the peak flow velocity at anastomosis (r=-0.078, P＞0.05). Pearson correlation analysis showed that the cephalic venous flow volume of AVF was correlated with the diameter ratio of the cephalic venous to radial artery and the anastomosis area (r=-0.671, r=0.482, both P＜0.05), and the wall shear stress (WSS) near the anastomosis was correlated with the anastomosis angle and wall thickness (r=0.530, r=0.462, both P＜0.05). Conclusion · 4D flow MRI can be used to evaluate the hemodynamic parameters of forearm AVF in renal dialysis patients, which can provide a reference for further study of AVF dysfunction.