Effects of statin on vascular diseases-inhibitory mechanism on intimal hyperplasia

他汀类药物对血管疾病的影响——内膜增生的抑制机制

基本信息

批准号：
17591326
负责人：
KOBAYASHI Masayoshi
金额：
$ 2.24万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591326/
关键词：
statin inhibition of intimal hyperplasia autologous vein graft Rho-kinesis eNOS midkine Rho-kinase

项目摘要

The efficacy of statin, a hydrophilic statin, pravastatin, and a lipohylic statin, pitavastatin, were evaluated on intimal hyperplasia, Rho-kinesis, and midkine expression of experimental normocholesterolemic rabbit autologous vein graft. Rabbit were fed regular rabbit chow, and pravastatin (10mg/kg/day), and pitavastatin (1mg/kg/day) was administered, respectively. A week after starting the treatment, juglar vein was implanted into the carotid artery. At 2 and 4 weeks after the operation, vein graft were harvested, and intimal hyperplasia of the vein grafts were assessed. Cell proliferation in neointima was detected by PCNA and Ki-67 stain 2 weeks after implantation. In addition, the effect of pitavastatin on midkine expression, a heparin-binding growth factor, in vein grafts was analyzed by Western blotting. And also the effect of pravastatin on human umbilical vein endothelial cells and vascular smooth muscle cells were examined by Westernblotting. We demonstrated that oral administ … More ration of both pravastatin and pitavastatin to normocholesterolemic rabbits inhibited intimal hyperplasia of carotid interposition-reversed juglar vein grafts after implantation and suppressed cell proliferation and apoptosis in theneointima. In addition, we found that pravasatatin inhibited Rho-kinase activity and accelerated endothelial nitric oxide synthase expression in human unbilical vein endothelial cells but did not inhibit Rho-kinase activity in vascular smooth muscle cells. As to pitavasatin, we found that pitavastatin inhibited midkine expression significantly in the vein grafts after implantationThese novel findings clearly demonstrated that both hydrophilic and lipohylic statin can suppress intimal hyperplasia of the vein graft in vivo, and a hydrophilic statin show endothelial cell-tropic inhibition of Rho-kinase in vitro, while a lipophilic statin show midkine inhibition. These results strongly support the clinical use of statins to prevent intimal hyperplasia of the vein graft after bypass grafting. Less

评估他汀类药物（一种亲水性他汀类药物普伐他汀）和一种脂亲性他汀类药物匹伐他汀对实验性正常胆固醇血症兔自体静脉移植物的内膜增生、Rho-运动和中期因子表达的功效。给兔子饲喂常规兔饲料和普伐他汀（10mg）。开始一周后分别给予匹伐他汀（1mg/kg/天）和匹伐他汀（1mg/kg/天）。治疗后2周和4周，将颈静脉植入颈动脉，采集静脉移植物，并通过PCNA和Ki-67染色2检测静脉移植物的内膜增生情况。此外，通过蛋白质印迹法分析了匹伐他汀对静脉移植物中中期因子（一种肝素结合生长因子）表达的影响。通过蛋白质印迹法检测普伐他汀对人脐静脉内皮细胞和血管平滑肌细胞的影响，结果表明，给正常胆固醇血症的兔子口服剂量的普伐他汀和匹伐他汀可抑制植入后颈动脉介入逆行颈静脉移植物的内膜增生，并抑制细胞增殖。此外，我们发现普伐他汀抑制 Rho 激酶。活性并加速人脐静脉内皮细胞中的内皮一氧化氮合酶表达，但不抑制血管平滑肌细胞中的Rho激酶活性至于匹伐他汀，我们发现匹伐他汀在植入后显着抑制静脉移植物中的中期因子表达这些新发现清楚地证明了。亲水性和亲脂性他汀类药物均可抑制体内静脉移植物的内膜增生，并且亲水性他汀类药物显示内皮体外对 Rho 激酶具有亲细胞性抑制作用，而亲脂性他汀类药物则表现出强烈的中期因子抑制作用。这些结果支持临床上使用他汀类药物来预防旁路移植术后静脉移植物的内膜增生。