The Stent-Eluting Drugs Sirolimus and Paclitaxel Suppress Healing of the Endothelium by Induction of Autophagy
The Stent-Eluting Drugs Sirolimus and Paclitaxel Suppress Healing of the Endothelium by Induction of Autophagy
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DOI：
10.2353/ajpath.2009.090152
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发表时间：
2009-11-01
影响因子：
6
通讯作者：
Nakashima, Shigeru
中科院分区：
文献类型：
--
作者：
Hayashi, Shin-ichiro;Yamamoto, Akitsugu;Nakashima, Shigeru
临床研究表明支架洗脱药物西罗莫司和紫杉醇影响再狭窄；然而，这些药物如何在分子和细胞水平上影响血管内皮仍不清楚。本研究的目的是确定西罗莫司和紫杉醇是否会诱导血管内皮细胞的分子和细胞改变。在人主动脉内皮细胞和大鼠主动脉内皮中评估内皮再生。通过蛋白质印迹分析、透射电子显微镜和免疫荧光染色分析人主动脉内皮细胞的分子和细胞变化。使用绿色荧光蛋白-LC3小鼠来分析自噬内皮。在这里，我们发现西罗莫司和紫杉醇差异性地诱导血管内皮细胞的自消化自噬，并改变 LC3B、P53 和 Bcl-2 的表达，从而显着抑制再内皮化和血运重建。这些结果表明西罗莫司或紫杉醇引起的内皮表型改变可能会影响晚期支架内血栓形成、心肌梗死和死亡率。 （Am J Pathol 2009，175：2226-2234；DOI：10.2353/ajpath.2009.090152）
Clinical studies have indicated that the stent-eluting drugs sirolimus and paclitaxel impact restenosis; however, it is still elusive how these drugs affect the vascular endothelium at the molecular and cellular levels. The purpose of this study was to determine whether sirolimus and paclitaxel induce molecular and cellular alterations in the vascular endothelium. Endothelial regrowth was assessed in human aortic endothelial cells and rat aortic endothelium. Molecular and cellular alterations were analyzed in human aortic endothelial cells by Western blot analysis, transmission electron microscopy, and immunofluorescence staining. Green fluorescent protein-LC3 mice were used to analyze autophagic endothelium. Here, we show that sirolimus and paclitaxel differentially induce self-digesting autophagy in vascular endothelial cells with changes in expression of LC3B, P53, and Bcl-2, considerably suppressing re-endothelialization and revascularization. These results suggest that phenotypic alteration in the endothelium by sirolimus or paclitaxel might affect the rates of late stent thrombosis, myocardial infarction, and mortality. (Am J Pathol 2009, 175:2226-2234; DOI: 10.2353/ajpath.2009.090152)