Anti-atherosclerotic effects of sirolimus on human vascular smooth muscle cells
Anti-atherosclerotic effects of sirolimus on human vascular smooth muscle cells
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DOI：
10.1152/ajpheart.01174.2006
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发表时间：
2007-06-01
影响因子：
4.8
通讯作者：
Varghese, Zac
中科院分区：
文献类型：
--
作者：
Ma, Kun L.;Ruan, Xiong Z.;Varghese, Zac
西罗莫司是一种有效的免疫抑制剂，通过其抗增殖特性具有抗动脉粥样硬化作用。本研究旨在研究在炎症细胞因子 IL-1 β 存在的情况下，西罗莫司对人血管平滑肌细胞 (VSMC) 细胞内胆固醇稳态的影响。我们通过油红 O 染色和细胞内胆固醇的定量测量，探讨了在 IL-1 β 存在的情况下西罗莫司对 VSMC 脂质积累的影响。分别通过实时 PCR 和蛋白质印迹检测西罗莫司对脂蛋白受体和 ATP 结合盒（ABCA1 和 ABCG1）的基因和蛋白表达的影响。此外，还使用[H-3]胆固醇流出研究了在存在或不存在IL-1β的情况下西罗莫司对胆固醇流出前VSMC的影响。最后。我们使用 ELISA 检查了西罗莫司对 VSMC 中炎症细胞因子产生的影响。西罗莫司减少 IL-1β 介导的 VSMC 细胞内脂质积累，可能是由于低密度脂蛋白 (LDL) 和极低密度脂蛋白 (VLDL) 受体表达的减少。西罗莫司增加 VSMC 的胆固醇流出，并克服 IL-1 β 诱导的胆固醇流出抑制。即使存在 IL-1 beta，西罗莫司也能增加 ABCA1 和 ABCG1 基因的表达。我们进一步证实西罗莫司抑制炎症细胞因子IL-6、肿瘤坏死因子-α、IL-S的RNA和蛋白表达。和单核细胞趋化蛋白-1。抑制脂质摄取以及增加胆固醇流出和抑制炎症细胞因子都是西罗莫司对 VSMC 抗动脉粥样硬化作用的重要方面。
Sirolimus is a potent immunossuppressive agent and has an anti-atherosclerotic effect through its anti-proliferative property. The present study was undertaken to investigate the effect of sirolimus on intracellular cholesterol homeostasis in human vascular smooth muscle cells (VSMCs) in the presence of inflammatory cytokine IL-1 beta. We explored the effect of sirolimus on the lipid accumulation of VSMCs in the presence of IL-1 beta, using Oil Red O staining and quantitative measurement of intracellular cholesterol. The effect of sirolimus on the gene and protein expression of lipoprotein receptors and ATP binding cassettes (ABCA1 and ABCG1) was examined by real-time PCR and Western blotting, respectively. Furthennore, the effect of sirolimus on cholesterol efflux front VSMCs in the presence or absence of IL-1 beta was also investigated using [H-3] cholesterol efflux. Finally. we examined the effect of sirolimus on the production of inflammatory cytokines in VSMCs using ELISA. Sirolimus reduced intracellular lipid accumulation in VSMCs mediated by IL-1 beta possibly due to the reduction of expression of low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) receptors. Sirolimus increased cholesterol efflux from VSMCs and overrode the suppression of cholesterol efflux induced by IL-1 beta. Sirolimus also increased ABCA1 and ABCG1 genes expression, even in the presence of IL-1 beta. We further confirmed that sirolimus inhibited rnRNA and protein expression of inflammatory cytokines IL-6, tumor necrosis factor-alpha, IL-S. and monocyte chemoattractant protein-1. Inhibition of lipid uptake together with increasing cholesterol efflux and the inhibition of inflammatory cytokines are all important aspects of the anti-atherosclerotic effects of sirolimus on VSMCs.