这项研究的目的是通过研究槲皮素对血管平滑肌细胞(VSMC)向巨噬细胞样细胞的表型转换和潜在的调节途径的影响来阐明槲皮素在动脉粥样硬化中的保护作用。高脂饮食(HFD)喂养的载脂蛋白E缺陷(ApoEKO)小鼠的主动脉组织,用或不用100mg/kg/天槲皮素治疗,分析了组织病理学变化和分子机制。发现槲皮素可减少动脉粥样硬化病变的大小并减轻HFD引起的脂质积累。荧光共定位分析显示与磷酸-Janus激酶2(p-JAK2)共定位的巨噬细胞样血管平滑肌细胞(VSMC)的存在更高,磷酸信号转导和转录激活因子3(p-STAT3),和Krüppel样因子4(KLF4)在主动脉斑块内的泡沫细胞聚集区域。然而,这种共定位在槲皮素治疗后减少.槲皮素治疗可有效抑制KLF4介导的氧化低密度脂蛋白(ox-LDL)负载小鼠主动脉血管平滑肌细胞(MOVAS)的表型转换,如KLF4,LGALS3,CD68和F4/80的表达降低,α平滑肌肌动蛋白(α-SMA)的表达增加,减少细胞内荧光Dil-ox-LDL摄取,和减少脂质积累。相比之下,APTO-253,一种KLF4激活剂,被发现可以逆转槲皮素的作用。此外,AG490,一种JAK2抑制剂,有效抵消ox-LDL诱导的JAK2/STAT3途径依赖性转换为巨噬细胞样表型和MOVAS细胞中的脂质积累。槲皮素可显着减轻这些作用,但JAK2激活剂CoumermycinA1可加剧这些作用。我们的研究表明,槲皮素抑制KLF4介导的VSMC向巨噬细胞样细胞的表型转换,并通过抑制JAK2/STAT3途径减少动脉粥样硬化。
The objective of this study was to elucidate the protective role of quercetin in atherosclerosis by examining its effect on the phenotypic switch of vascular smooth muscle cells (VSMCs) to macrophage-like cells and the underlying regulatory pathways. Aorta tissues from apolipoprotein E-deficient (ApoE KO) mice fed a high-fat diet (HFD), treated with or without 100 mg/kg/day quercetin, were analyzed for histopathological changes and molecular mechanisms. Quercetin was found to decrease the size of atherosclerotic lesions and mitigate lipid accumulation induced by HFD. Fluorescence co-localization analysis revealed a higher presence of macrophage-like vascular smooth muscle cells (VSMCs) co-localizing with phospho-Janus kinase 2 (p-JAK2), phospho-signal transducer and activator of transcription 3 (p-STAT3), and Krüppel-like factor 4 (
KLF4) in regions of foam cell aggregation within aortic plaques. However, this co-localization was reduced following treatment with quercetin. Quercetin treatment effectively inhibited the
KLF4-mediated phenotypic switch in oxidized low-density lipoprotein (ox-LDL)-loaded mouse aortic vascular smooth muscle cells (MOVAS), as indicated by decreased expressions of
KLF4, LGALS3, CD68, and F4/80, increased expression of alpha smooth muscle actin (α-SMA), reduced intracellular fluorescence Dil-ox-LDL uptake, and decreased lipid accumulation. In contrast, APTO-253, a
KLF4 activator, was found to reverse the effects of quercetin. Furthermore, AG490, a JAK2 inhibitor, effectively counteracted the ox-LDL-induced JAK2/STAT3 pathway-dependent switch to a macrophage-like phenotype and lipid accumulation in MOVAS cells. These effects were significantly mitigated by quercetin but exacerbated by coumermycin A1, a JAK2 activator. Our research illustrates that quercetin inhibits the
KLF4-mediated phenotypic switch of VSMCs to macrophage-like cells and reduces atherosclerosis by suppressing the JAK2/STAT3 pathway.