Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
J Am Coll Cardiol. 2009 Dec 8;54(24):2321-9. doi: 10.1016/j.jacc.2009.07.045.
This study examined whether the Rho-kinase pathway is involved in the pathogenesis of coronary hyperconstricting responses induced by drug-eluting stents (DES) in pigs in vivo.
Recent studies showed that coronary vasoconstricting responses are enhanced at the edge of coronary segments implanted with DES compared with bare-metal stents (BMS) in humans. We have previously shown that the activated Rho-kinase pathway plays a central role in the molecular mechanism of coronary vasospasm in animals and humans.
Human coronary artery smooth muscle cells (hCASMCs) were coincubated with various concentrations of paclitaxel (10(-9) to 10(-6) mol/l, corresponding levels reported in DES-implanted arterial tissue) for 24 h. A paclitaxel-eluting stent (PES), sirolimus-eluting stent (SES), and BMS were randomly implanted in the left coronary arteries in pigs for 4 weeks.
In hCASMCs, paclitaxel significantly enhanced Rho-kinase expression and activity. In a porcine model, coronary vasoconstricting responses to serotonin (10 and 100 microg/kg intracoronary administration) were significantly enhanced at the PES site compared with the BMS site (45+/-4% vs. 30+/-3%; p<0.01; n=12 each), and were abolished by hydroxyfasudil (90 and 300 microg/kg intracoronary administration), a selective Rho-kinase inhibitor. The PES enhanced inflammatory responses and microthrombus formation at the stent edge, where immunoreactivities for Rho-kinase expression and activity were increased. In organ chamber experiments, serotonin-induced contractions were significantly enhanced in rings from the PES edge site compared with the BMS edge site. The SES also caused similar coronary hyperconstricting responses to serotonin in vivo.
These results suggest that the Rho-kinase pathway plays an important role in the pathogenesis of DES-induced coronary hyperconstricting responses.
本研究旨在探讨 Rho 激酶通路是否参与了体内猪药物洗脱支架（DES）诱导的冠状动脉痉挛反应的发病机制。
最近的研究表明，与裸金属支架（BMS）相比，DES 植入的冠状动脉节段边缘的冠状动脉收缩反应增强。我们之前已经表明，在动物和人类中，激活的 Rho 激酶通路在冠状动脉痉挛的分子机制中起核心作用。
将人冠状动脉平滑肌细胞（hCASMCs）与不同浓度的紫杉醇（10（-9）至 10（-6）mol/L，对应于报道的 DES 植入动脉组织中的浓度）共同孵育 24 小时。将紫杉醇洗脱支架（PES）、西罗莫司洗脱支架（SES）和 BMS 随机植入猪的左冠状动脉 4 周。
在 hCASMCs 中，紫杉醇显著增强了 Rho 激酶的表达和活性。在猪模型中，与 BMS 部位相比，PES 部位对 5-羟色胺（10 和 100μg/kg 冠状动脉内给予）的冠状动脉收缩反应明显增强（45+/-4%比 30+/-3%；p<0.01；n=12 例），并被选择性 Rho 激酶抑制剂羟法舒地尔（90 和 300μg/kg 冠状动脉内给予）所消除。PES 增强了支架边缘的炎症反应和微血栓形成，支架边缘处 Rho 激酶表达和活性的免疫反应性增加。在器官室实验中，与 BMS 边缘部位相比，来自 PES 边缘部位的 5-羟色胺诱导的收缩明显增强。SES 也导致体内 5-羟色胺引起的类似冠状动脉收缩反应。
这些结果表明，Rho 激酶通路在 DES 诱导的冠状动脉收缩反应的发病机制中起重要作用。
