The Activation of Wnt Signaling Facilitates Autophagy by Modulating GSK-3β-AMPK Axis in Atherosclerosis
Molecular & Cellular Toxicology/Molecular & cellular toxicology(2022)
Abstract
Endothelial dysfunction induced by oxidized low-density lipoprotein (ox‐LDL) is implicated in the pathogenesis of atherosclerosis (AS). Activated autophagy was reported to improve endothelial functions and alleviate AS development. AMPK is a key protein in the regulation of autophagy, which can be modulated by Wnt signaling pathway. Our study was designed to explore whether the canonical Wnt activator Wnt3a promotes autophagy in AS through in vitro and in vivo assays. Human umbilical vein endothelial cells (HUVECs) were first treated with ox‐LDL at 50 μg/mL for 24 h and then transfected with Wnt3a-overexpressed plasmid pcDNA3.1/Wnt3a. At 48 h after transfection, HUVECs were treated with 100 μM 3-MA. To investigate the effects of GSK-3β inhibition on the activation of AMPK, HUVECs were treated with 10 μM TWS119. Cell viability was detected via Trypan blue staining. Wnt3a expression, autophagy markers, GSK-3β inhibition and AMPK activation were examined by western blotting. To induce animal model of AS, male apolipoprotein E deficient (ApoE−/−) mice were fed with high-fat diet. pcDNA3.1/Wnt3a was injected into ApoE−/− mice after high-fat diet induction. Oil Red O staining was performed to examine lipid and plaque deposition in atherosclerotic lesions. In this study, ox‐LDL treatment decreased HUVEC viability and downregulated Wnt3a expression. Wnt3a overexpression promoted autophagy, induced GSK-3β phosphorylation at Ser9, and AMPK phosphorylation at Thr172 in ox-LDL-stimulated HUVECs. Overexpressing Wnt3a ameliorated lipid accumulation in aortic plaque of ApoE−/− mice. Furthermore, Wnt3a overexpression also activated autophagy, and induced GSK-3β and AMPK phosphorylation in ApoE−/− mice. Wnt3a activates AMPK through inhibiting GSK-3β, thereby facilitating autophagy in AS.
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Key words
Atherosclerosis,Wnt/GSK-3β signaling,AMPK,Endothelial dysfunction,Autophagy
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