曲尼司特通过p21waf1依赖通路减少平滑肌细胞增生的小鼠遗传证据

M. Sata, A. Takahashi, Kimie Tanaka, Miwa Washida, N. Ishizaka, J. Ako, M. Yoshizumi, Y. Ouchi, T. Taniguchi, Y. Hirata, M. Yokoyama, R. Nagai, K. Walsh
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引用次数: 20

摘要

目的:n -(3 ' 4 ' -二甲氧基肉桂酰)-邻氨基苯酸(曲尼司特)是一种在中等规模临床试验中被证明可以降低血管成形术后再狭窄发生率的药物。尽管临床上对这种药物感兴趣,曲尼司特的药理作用在分子水平上仍然相对未被探索。方法和结果:我们在缺乏细胞周期蛋白依赖性激酶抑制剂p21WAF1 (p21)的野生型小鼠和小鼠中评估曲尼司特对血管平滑肌细胞(VSMC)增殖的影响。曲尼司特能有效抑制野生型小鼠的VSMC培养物的增殖,但来自p21缺陷(p21−/−)小鼠的VSMC不受这种处理的影响。在小鼠股动脉血管损伤模型中,通过增殖细胞核抗原的免疫染色测定,曲尼司特给药野生型小鼠导致p21表达上调和增殖性VSMCs数量减少。相比之下,曲尼司特对p21−/−小鼠损伤动脉中增殖细胞核抗原阳性细胞的数量没有影响。曲尼司特可显著降低野生型小鼠在4周时的新生内膜VSMC增生,但对p21−/−小鼠的病变形成没有影响。结论:我们的研究结果提供了遗传学证据,曲尼司特通过p21依赖途径抑制内膜增生,这一活性可能有助于其预防血管成形术后再狭窄的疗效。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Mouse Genetic Evidence That Tranilast Reduces Smooth Muscle Cell Hyperplasia via a p21WAF1-Dependent Pathway
Objective—N-(3′4′-dimethoxycinnamoyl)-anthranilic acid (tranilast) is a drug that has been shown to reduce the incidence of restenosis after angioplasty in middle-scale clinical trials. Despite clinical interest in this drug, the pharmacological actions of tranilast remain relatively unexplored at a molecular level. Methods and Results—We evaluated the effects of tranilast on vascular smooth muscle cell (VSMC) proliferation in wild-type mice and in mice lacking a cyclin-dependent kinase inhibitor, p21WAF1 (p21). Tranilast potently inhibited the proliferation of VSMC cultures derived from wild-type mice, but VSMCs derived from p21-deficient (p21−/−) mice were unaffected by this treatment. In a mouse femoral artery model of vascular injury, tranilast administration to wild-type mice led to an upregulation of p21 expression and a decrease in the number of proliferating VSMCs, as determined by immunostaining for proliferating cell nuclear antigen. In contrast, tranilast had no effect on the number of proliferating cell nuclear antigen–positive cells in the injured arteries of p21−/− mice. Administration of tranilast significantly reduced the neointimal VSMC hyperplasia in wild-type mice at 4 weeks but had no effect on lesion formation in p21−/− mice. Conclusions—Our findings provide genetic evidence that tranilast inhibits intimal hyperplasia via a p21-dependent pathway, an activity that may contribute to its efficacy in the prophylactic treatment of postangioplasty restenosis.
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