School of Pharmacy, Taipei Medical University, Taipei, 110, Taiwan.
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089, USA.
Phytother Res. 2018 Feb;32(2):312-320. doi: 10.1002/ptr.5979. Epub 2017 Dec 18.
Neointimal hyperplasia (or restenosis) is primarily attributed to excessive proliferation and migration of vascular smooth muscle cells (VSMCs). In this study, we investigated the inhibitory effects and mechanisms of ugonin J on VSMC proliferation and migration as well as neointimal formation. Cell viability and the cell-cycle distribution were, respectively, analyzed using an MTT assay and flow cytometry. Cell migration was examined using a wound-healing analysis and a transwell assay. Protein expressions and gelatinase activities were, respectively, measured using Western blot and gelatin zymography. Balloon angioplasty-induced neointimal formation was induced in a rat carotid artery model and then examined using immunohistochemical staining. Ugonin J induced cell-cycle arrest at the G /G phase and apoptosis to inhibit VSMC growth. Ugonin J also exhibited marked suppressive activity on VSMC migration. Ugonin J significantly reduced activations of focal adhesion kinase, phosphoinositide 3-kinase, v-akt murine thymoma viral oncogene homolog 1, and extracellular signal-regulated kinase 1/2 proteins. Moreover, ugonin J obviously reduced expressions and activity levels of matrix metalloproteinase-2 and matrix metalloproteinase-9. In vivo data indicated that ugonin J prevented balloon angioplasty-induced neointimal hyperplasia. Our study suggested that ugonin J has the potential for application in the prevention of balloon injury-induced neointimal formation.
血管平滑肌细胞（VSMCs）的过度增殖和迁移是导致新生内膜增生（或再狭窄）的主要原因。在本研究中，我们研究了乌骨藤甲素对 VSMC 增殖、迁移和新生内膜形成的抑制作用及其机制。分别采用 MTT 法和流式细胞术分析细胞活力和细胞周期分布。采用划痕愈合分析和 Transwell 测定法检测细胞迁移。采用 Western blot 和明胶酶谱法分别测定蛋白表达和明胶酶活性。采用免疫组织化学染色法检测大鼠颈总动脉球囊损伤模型中的新生内膜形成。乌骨藤甲素诱导细胞周期停滞在 G0/G1 期并诱导细胞凋亡，从而抑制 VSMC 生长。乌骨藤甲素对 VSMC 迁移也具有明显的抑制作用。乌骨藤甲素显著降低了黏着斑激酶、磷酸肌醇 3-激酶、v-akt 鼠胸腺瘤病毒癌基因同源物 1 和细胞外信号调节激酶 1/2 蛋白的激活。此外，乌骨藤甲素明显降低了基质金属蛋白酶-2 和基质金属蛋白酶-9 的表达和活性水平。体内数据表明，乌骨藤甲素可预防球囊血管成形术后引起的新生内膜增生。我们的研究表明，乌骨藤甲素具有预防球囊损伤诱导的新生内膜形成的潜力。
