Hydrophilic statin suppresses vein graft intimal hyperplasia via endothelial cell-tropic Rho-kinase inhibition
Hydrophilic statin suppresses vein graft intimal hyperplasia via endothelial cell-tropic Rho-kinase inhibition
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DOI：
10.1016/j.jvs.2005.05.041
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发表时间：
2005-10-01
影响因子：
4.3
通讯作者：
Komori, K
中科院分区：
文献类型：
--
作者：
Yamanouchi, D;Banno, H;Komori, K
背景资料：最近的研究表明，他汀类药物可以通过抑制小的三磷酸鸟苷结合蛋白、Rho和Rho相关激酶，以独立于其降脂活性的方式保护血管系统。关于他汀类药物对静脉移植物内膜增生的抑制作用的信息很少，静脉移植物内膜增生是旁路移植术后晚期移植物失败的主要原因。因此，我们研究了一个亲水性他汀类药物对静脉移植物内膜增生在体内和Rho-激酶activityinvitro.Methods的影响：在第一个实验中，兔被随机分为对照组（n = 7），这是喂养普通兔饲料或普伐他汀组（n = 7），这是喂养普通兔饲料补充10 mg/kg普伐他汀钠。结扎颈静脉分支，取约3 cm的颈静脉段用于自体反向静脉移植。切断颈动脉，并用收获的自体颈静脉置换。分别于术后2周和4周取静脉移植物，观察移植物内膜增生情况。在第二个实验中，培养人脐静脉内皮细胞和血管平滑肌细胞，然后用1 μ mol/L和30 μ mol/L普伐他汀处理24小时并收获。对所得沉淀物进行免疫印迹。通过光密度分析对磷酸化肌球蛋白结合亚基和内皮型一氧化氮合酶进行定量评价。我们证明，对胆固醇正常的家兔口服亲水性他汀类药物普伐他汀可抑制植入后4周颈动脉间置-反向颈静脉移植物的内膜增生（普伐他汀组，39.5 +/- 3.5 μ m vs对照组，64.0 +/- 7.1 μ m; n = 7; P
Background: Recent studies suggest that statins can protect the vasculature in a manner that is independent of their lipid-lowering activity through inhibition of the small guanosine triphosphate-binding protein, Rho, and Rho-associated kinase. Little information is available on the inhibitory effect of statins on vein graft intimal hyperplasia, the main cause of late graft failure after bypass grafting. We therefore examined the effects of a hydrophilic statin on vein graft intimal hyperplasia in vivo and Rho-kinase activity in vitro.Methods: In the first experiment, rabbits were randomized to a control group (n = 7) that was fed regular rabbit chow or to a pravastatin group (n = 7) that was fed regular rabbit chow supplemented with 10 mg/kg pravastatin sodium. The branches of the jugular vein were ligated and an approximately 3-cm segment of the jugular vein was taken for an autologous reversed-vein graft. The carotid artery was cut and replaced with the harvested autologous jugular vein. At 2 and 4 weeks after the operation, vein grafts in both groups were harvested, and intimal hyperplasia of the vein grafts was assessed. In the second experiment, human umbilical vein endothelial cells and vascular smooth muscle cells were cultured and then treated with 1 mu mol/L and 30 mu mol/L pravastatin for 24 hours and harvested. Immunoblotting was performed on the resulting precipitates. Quantitative evaluation of phosphorylated myosin binding subunit and endothelial nitric oxide synthase was performed by densitometric analysis.Results: We demonstrated that oral administration of the hydrophilic statin pravastatin to normocholesterolemic rabbits inhibited intimal hyperplasia of carotid interposition-reversed jugular vein grafts 4 weeks after implantation (pravastatin group, 39.5 +/- 3.5 mu m vs control group, 64.0 +/- 7.1 mu m; n = 7; P