Atherosclerosis (AS) is characterized by lipids metabolism disorder and inflammatory response. Accumulating evidence has demonstrated that Wingless type 5a (Wnt5a) is implicated in cardiovascular diseases through non-canonical Wnt cascades. However, its precise role during the pathogenesis of AS is still unclear. Therefore, the present study aims to investigate the role and the underlying mechanism of Wnt5a/receptor tyrosine kinase-like orphan receptor 2 (Ror2) pathways in the promotion of AS process through affecting lipid accumulation and inflammation. In atherosclerotic clinical samples, Wnt5a levels were measured by using enzyme-linked immunosorbent assay (ELISA) assay. In vivo experiments were conducted by using apolipoprotein E knockout (apoE-/-) mice model. Vascular smooth muscle cells (VSMCs) were applied for in vitro studies. Wnt5a was highly expressed in both of atherosclerotic clinical samples and apoE-/- mice. The knockdown of Wnt5a significantly inhibited cholesterol accumulation and inflammatory response. Additionally, the lipopolysaccharide (LPS)-induced inflammation aggravated the cholesterol accumulation and decreased adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) expression in VSMCs. Depletion of intracellular cholesterol by β-cyclodextrin (β-CD) led to the upregulation of ABCA1 and the inhibition of inflammation. Conversely, the overexpression of Wnt5a inhibited ABCA1 expression, facilitated cholesterol accumulation, impared cholesterol efflux, promoted NF-κB nuclear translocation and the inflammatory cytokines secretion. Moreover, the knockdown of Ror2 increased ABCA1 expression and reduced Wnt5a-induced cholesterol accumulation and inflammatory responses. Furthermore, the knockdown of ABCA1 enhanced cholesterol accumulation and inflammatory response. Therefore, Wnt5a/Ror2 pathway was critical in regulating cholesterol homeostasis and inflammatory response, which might be a promising therapeutic target for AS therapy.

中文翻译：

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Wnt5a / Ror2通路有助于调节动脉粥样硬化中的胆固醇稳态和炎症反应。

动脉粥样硬化（AS）的特点是脂质代谢紊乱和炎症反应。越来越多的证据表明，无翅5a型（Wnt5a）通过非经典Wnt级联参与了心血管疾病。但是，其在AS发病机理中的确切作用仍不清楚。因此，本研究旨在研究Wnt5a /受体酪氨酸激酶样孤儿受体2（Ror2）途径在通过影响脂质蓄积和炎症促进AS过程中的作用及其潜在机制。在动脉粥样硬化临床样品中，通过使用酶联免疫吸附测定（ELISA）测定来测量Wnt5a水平。体内实验是通过使用载脂蛋白E基因敲除（apoE-/-）小鼠模型进行的。血管平滑肌细胞（VSMC）用于体外研究。Wnt5a在动脉粥样硬化临床样品和apoE-/-小鼠中均高表达。敲低Wnt5a显着抑制胆固醇积累和炎症反应。此外，脂多糖（LPS）引起的炎症加剧了VSMC中的胆固醇蓄积，并降低了三磷酸腺苷（ATP）结合盒转运蛋白A1（ABCA1）的表达。β-环糊精（β-CD）消耗细胞内胆固醇会导致ABCA1上调并抑制炎症。相反，Wnt5a的过表达抑制了ABCA1的表达，促进了胆固醇的积累，降低了胆固醇的外流，促进了NF-κB核易位和炎性细胞因子的分泌。而且，Ror2的敲低会增加ABCA1表达，并减少Wnt5a诱导的胆固醇蓄积和炎症反应。此外，敲低ABCA1可以增强胆固醇蓄积和炎症反应。因此，Wnt5a / Ror2通路在调节胆固醇稳态和炎症反应中至关重要，这可能是AS治疗的有希望的治疗靶点。