Stent implantation activates RhoA in human arteries:: Inhibitory effect of rapamycin
Stent implantation activates RhoA in human arteries:: Inhibitory effect of rapamycin
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DOI：
10.1159/000082873
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发表时间：
2005-01-01
影响因子：
1.7
通讯作者：
Loirand, G
中科院分区：
文献类型：
--
作者：
Guérin, P;Sauzeau, V;Loirand, G
支架内再狭窄是由血管平滑肌细胞（VSMC）增殖、迁移和过度基质产生引起的一种新的病理生物学过程。本研究旨在评估支架植入后 VSMC 增殖和迁移的主要调节因子 RhoA 的活性，并确定其在新内膜形成中的作用。对人内乳动脉离体器官培养模型中 RhoA 活性的分析表明，支架置入会导致 RhoA 活性随时间依赖性增加（28 天时对照中为 4.9 +/- 0.4 对比 1.2 +/- 0.2，n = 4，p < 0.0001），并伴随 p27 表达减少。用渗透性RhoA抑制剂TAT-C3（10μg/ml）或Rho激酶抑制剂（Y-27632，10μmol/l；法舒地尔，10μmol/l）治疗支架动脉可抑制新内膜形成并减少p27表达。雷帕霉素（1 和 10 nmol/l）也抑制新内膜形成，并诱导 RhoA 表达丧失。雷帕霉素对新内膜增厚的抑制作用被 RhoA 的主要活性形式所阻止。我们的研究表明支架植入可诱导维持 RhoA 激活，并证明雷帕霉素对 RhoA 表达的抑制作用在其抗再狭窄作用中起着关键作用。版权所有 (C) 2005 S. Karger AG，巴塞尔。
In- stent restenosis is a novel pathobiologic process resulting from vascular smooth muscle cell ( VSMC) proliferation, migration and excessive matrix production. The present study was designed to assess the activity of RhoA, a major regulator of VSMC proliferation and migration, after stenting and to determine its role in the neointimal formation. Analysis of RhoA activity in an ex vivo organ culture model of human internal mammary arteries demonstrates that stenting induced a time-dependent increase in RhoA activity ( 4.9 +/- 0.4 vs. 1.2 +/- 0.2 in control at 28 days, n = 4, p < 0.0001) associated with a concomitant decrease in p27 expression. Treatment of stented arteries with the permeant RhoA inhibitor TAT- C3 ( 10 mu g/ ml) or Rho- kinase inhibitors ( Y- 27632, 10 mu mol/ l; fasudil, 10 mu mol/ l) inhibited both neointimal formation and decrease in p27 expression. Rapamycin ( 1 and 10 nmol/ l) also inhibited neointimal formation, and induced a loss of RhoA expression. The inhibitory effect of rapamycin on neointimal thickening is prevented by the dominant active form of RhoA. Our study shows that stent implantation induces maintained RhoA activation and demonstrates that the inhibitory action of rapamycin on RhoA expression plays a key role in its antirestenotic effect. Copyright (C) 2005 S. Karger AG, Basel.