Quercetin Attenuates Atherosclerosis via Modulating Oxidized LDL-Induced Endothelial Cellular Senescence
Quercetin Attenuates Atherosclerosis via Modulating Oxidized LDL-Induced Endothelial Cellular Senescence
复制标题
槲皮素通过调节氧化低密度脂蛋白诱导的内皮细胞衰老减轻动脉粥样硬化
DOI：
10.3389/fphar.2020.00512
复制
发表时间：
2020-04-28
影响因子：
5.6
通讯作者：
Li, Xiao
中科院分区：
文献类型：
--
作者：
Jiang, Yue-Hua;Jiang, Ling-Yu;Li, Xiao
背景和目的内皮衰老是导致动脉粥样硬化的重要危险因素。槲皮素抗内皮衰老的机制值得探讨。方法给ApoE-/-小鼠灌胃槲皮素（20 mg/kg/d），评价槲皮素对体内动脉粥样硬化病变的作用。在体外，使用人主动脉内皮细胞（HAEC）评估槲皮素对氧化低密度脂蛋白（ox-LDL）诱导的细胞衰老的影响。采用转录组微阵列和定量RT-PCR来研究槲皮素的药理靶点。结果ApoE-/-小鼠动脉腔内有明显的脂质沉积，血清sIcam-1和IL-6水平较高，主动脉内Vcam-1密度较高，Sirt1密度较低。槲皮素给药可减少 ApoE-/- 小鼠动脉腔、血清 sIcam-1 以及主动脉 IL-6 和 Vcam-1 中的脂质沉积，同时增加 ApoE-/- 小鼠主动脉中 Sirt1 的密度。在体外，槲皮素（0.3、1或3 μmol/L）降低衰老相关β-半乳糖苷酶的表达，改善HAECs的细胞形态。槲皮素以剂量依赖性方式减少细胞凋亡并增加线粒体膜电位（ΔΨm），同时减少ROS的产生。转录组微阵列显示，槲皮素处理后，HAEC 中有 254 个差异表达 (DE) mRNA（110 个 mRNA 上调，144 个 mRNA 下调）（倍数变化 > 1.5，P < 0 .05，Que 与 Ox-LDL）。 GO和KEGG分析表明氮代谢、ECM-受体相互作用、补体和凝血级联、p53和mTOR信号通路参与了槲皮素抗ox-LDL的药理机制。结论槲皮素在体内和体外均能减轻动脉粥样硬化病变。
Background and Aims Endothelial senescence is an important risk factor leading to atherosclerosis. The mechanism of quercetin against endothelial senescence is worth exploring. Methods Quercetin (20 mg/kg/d) was administered to ApoE-/- mice intragastrically to evaluate the effectiveness of quercetin on atherosclerotic lesion in vivo. In vitro, human aortic endothelial cells (HAECs) were used to assess the effect of quercetin on cellular senescence induced by oxidized low-density lipoprotein (ox-LDL). Transcriptome microarray and quantitative RT-PCR was conducted to study the pharmacological targets of quercetin. Results ApoE-/- mice demonstrated obvious lipid deposition in arterial lumina, high level of serum sIcam-1 and IL-6, and high density of Vcam-1 and lower density of Sirt1 in aorta. Quercetin administration decreased lipid deposition in arterial lumina, serum sIcam-1, and IL-6 and Vcam-1 in aorta, while increased the density of Sirt1 in aorta of ApoE-/- mice. In vitro, quercetin (0.3, 1, or 3 μmol/L) decreased the expression of senescence-associated β-galactosidase and improved cell morphology of HAECs. And quercetin decreased the cellular apoptosis and increased mitochondrial membrane potential (ΔΨm) in dose-dependent manner, and decreased ROS generation simultaneously. Transcriptome microarray suggested 254 differentially expressed (DE) mRNAs (110 mRNAs were upregulated and 144 mRNAs were downregulated) in HAECs after quercetin treatment (fold change > 1.5, P < 0 .05, Que vs Ox-LDL). GO and KEGG analysis indicated nitrogen metabolism, ECM-receptor interaction, complement, and coagulation cascades, p53 and mTOR signaling pathway were involved in the pharmacological mechanisms of quercetin against ox-LDL. Conclusions Quercetin alleviated atherosclerotic lesion both in vivo and in vitro.