The novel role and underlying mechanism of Wnt5a in regulating cellular cholesterol accumulation

Abstract

Cholesterol accumulation is a critical step during the development and progression of atherosclerosis. Recently, Wnt5a expression has been found to be markedly upregulated in both murine and human atherosclerotic lesions. However, the effect and mechanism of Wnt5a in atherosclerosis is poorly understood. In the present study, we investigated the effects and potential mechanisms of Wnt5a on cholesterol accumulation during atherosclerosis. We used RAW264.7 and vascular smooth muscle cells (VSMC) treated with oxidized low-density lipoprotein (oxLDL) as lipid-loaded cell models. We found that expression of Wnt5a protein was increased in a concentration (25, 50, 75 and 100 μg/mL)- and time (24, 48 and 72 h)-dependent manner by oxLDL treatment. To explore the underlying mechanism, we used Wnt5a short interference (si) RNA to knockdown Wnt5a expression in both RAW264.7 cells and VSMC, or applied recombinant Wnt5a (rWnt5a) to stimulate Wnt5a signalling. After Wnt5a knockdown, total cholesterol (TC) and free cholesterol (FC) content in both cell types increased significantly (P < 0.05) upon exposure to oxLDL. Conversely, the TC and FC content decreased markedly (P < 0.05) after treatment of cells with rWnt5a. More importantly, both protein and mRNA expression of Caveolin-1 and ATP-binding cassette transporter A1 (ABCA1) was significantly reduced after exposure of wnt5a siRNA-treated cells to oxLDL, whereas rWnt5a treatment of cells resulted in increased Caveolin-1 and ABCA1 protein expression after exposure of cells to oxLDL. Together, these findings demonstrate, for the first time, that Wnt5a reduces the accumulation of cholesterol in lipid-loaded cells by regulating the mRNA expression of Caveolin-1 and ABCA1, which are involved in reverse cholesterol transport. This may present a novel mechanism of Wnt5a-mediated cholesterol transportation in macrophages and VSMC. Therefore, targeting the Wnt5a signalling pathway may have clinical implications in atherosclerosis.

Wnt5a: A player in the pathogenesis of atherosclerosis and other inflammatory disorders

“…The results indicate that on average, the amount of Wnt5a protein present in the serum of atherosclerotic patients was significantly higher compared to that of healthy controls [36]. Recently, Wnt5a was shown to be involved in the regulation of cholesterol accumulation in mouse macrophages [37]. This finding is in line with results from our lab that show that Wnt5a modulates the expression of scavenger receptors in THP-1 cells, suggesting a role for Wnt5a during foam cell formation [38].…”

“…In the early stages of atherosclerosis, inflammation of the endothelial wall can activate the endothelial cells to secret Wnt5a, and this Wnt5a could play an important role in the recruitment of monocytes to the site of injury [39]. Additionally, based on the recently reported role of Wnt5a in cholesterol accumulation, it is possible that Wnt5a may contribute in the formation of foam cells [37, 66]. During acute events or complications developed in vulnerable atherosclerotic plaques, Wnt5a may play a role as an inflammatory regulator by modulating the expression of biological mediators like IL-6, IL-1β, cyclooxygenase-2 etc.…”

Wnt signaling in cardiovascular disease: opportunities and challenges

“…Recent data suggests that upregulation of Abca1 by Wnt5a in RAW264.7 myeloid cells following oxLDL treatment reduces lipid accumulation via enhanced reverse cholesterol transport[131]. Similarly, Boucher, Herz, and colleagues have shown that Wnt5a upregulates Abcg1 and inhibits 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase and synthetase in mouse embryonic fibroblasts, thereby limiting the intracellular accumulation of cholesterol[132].…”

Functional Regression Models for Epistasis Analysis of Multiple Quantitative Traits

“…Among 42 pathways, in the previous sections we reported that 14 pathways were associated with HDL and LDL. From the literatures, we also know that unsaturated fatty acids stimulated the uptake of the LDL particles [ 53 ], PPAR signaling pathway was correlated with blood pressure [ 54 ], purine metabolism was associated with SBP [ 55 ], Wnt signaling pathway mediated cholesterol transportation [ 56 ], glycerolipid metabolism pathway was correlated with total cholesterol [ 57 ], focal adhesion pathway was involved in lipid modulation [ 58 ], Cell adhesion molecules was correlated with blood pressure [ 59 ].…”