辛伐他汀对支架置入后兔腹主动脉内膜增生的影响Effect of simvastatin on intimal proliferation in abdominal aorta of rabbits after stenting
许文克,高传玉,于洁
摘要(Abstract)：
目的观察辛伐他汀对兔腹主动脉支架置入后内膜增殖的影响。方法30只新西兰大白兔随机分为对照组和辛伐他汀治疗组。采用含1.5%胆固醇的高脂饮食加腹主动脉内皮剥脱术制作兔腹主动脉粥样硬化模型。内皮剥脱术后第12周实验组和对照组服用阿司匹林25mg/d,氯吡格雷12.5mg/d,3d后,分别行支架置入术。术后实验组继续服用辛伐他汀5mg/d,服药至第30天处死动物,取腹主动脉含支架段血管,进行血管壁组织形态学变化观察和检测细胞周期抑制蛋白P27kip1、增殖细胞核抗原(PCNA)在各组的表达量的变化。结果血管超声发现内皮剥脱术后第10周实验组和对照组腹主动脉均可见有不同程度的粥样硬化斑块和血管内狭窄。组织形态学观察发现服用辛伐他汀的实验组兔腹主动脉支架段内的血管内膜厚度(0.107±0.072mm,与对照组0.133±0.047mm比,P=0.006)、新生内膜面积(0.975±0.084mm2,与对照组1.350±0.043mm2比,P=0.001)均明显降低,且血管的狭窄程度较轻(20.460%±2.325%,与对照组31.020%±1.904%比,P=0.002)。实验组兔腹主动脉支架段内的血管新生内膜中的血管平滑肌细胞(VSMC)的胞核P27kipl蛋白表达量明显升高(7.149±0.305,与对照组2.997±0.310比,t=9.551,P<0.05),而血管新生内膜中VSMC的胞核PCNA表达量明显降低(着色强度IS为3.003±0.192,与对照组着色强度IS5.268±0.475比,t=4.423,P<0.05)。结论辛伐他汀能明显抑制支架置入术后血管内膜增生。其机制可能为通过上调P27kip1蛋白表达量,使增殖标志物PCNA表达量降低,而对VSMC增殖周期起负调控作用,达到抑制VSMC增殖和新生内膜的增生。
关键词(KeyWords)： 动脉粥样硬化;支架;辛伐他汀;细胞周期蛋白质类;增殖细胞核抗原
基金项目(Foundation):
作者(Author): 许文克,高传玉,于洁
参考文献(References)：
- [1]Susebedk T,Latsch A,Ski H,et al.Role of vessel size as a pre-dictor for the occurrence of instent restenosis in patients with dia-betes mellitus.Am J Cardiol,2001,88:243-247.
- [2]Williams DO,Holubkov R,Yeh W,et al.Percutaneous coro-nary intervention in the current era compared with1985-1986:the National Heart,Lung,and Blood Institute Registries.Circula-tion,2000,102:2945-2951.
- [3]Franklin SM,Faxon DP.Pharmacologic prevention of restenosis after coronary angioplasty:review of the randomized clinical tri-als.Coron Artery Dis,1993,4:432-442.
- [4]Scandinavian Simuastatin Survival Study Group.Random-ized tri-al of cholesterol lowiny in4444patients with coronany heart dis-ease.The Scandinavian Simvastatin Survival Study(45).Lan-cet,1994,344:1383-1389.
- [5]Schneider JE,Berk BC,Gravanis MB,et al.Probucol decreases neointimal formation in a swine model of coronary artery balloon injure.Circulation,1993,88:628-637.
- [6]Bresalier RS,Ho SB,Schoeppner HL,et al.Enhanced sialylation of mucin-associated carbohy-drate structures In human colon can-cermentastasis.Gastroenterol,1996,110:1354-1367.
- [7]Kornowski R,Hong MK,Fermin OT,et al.In-stent restenosis:contributions of inflammatory responses and arterial injury to neointima hyperplasia.J Am Coll Cardiol,1998,31:224-230.
- [8]Indolfi C,MongiardoA,CurcioA,et al.Molecular mechanisms of in-stent restenosis and approach to therapy with eluting stents.Trend Cardiovasc Med,2003,13:142-148.
- [9]Erl W,Hristov M,Neureuter M,et al.HMG-CoAreductase inhib-itors induce apoptosis in neointim aderived vascular smooth mus-cle cells.Atherosclerosis,2003,169:251-258.
- [10]Laufs U,Marra D,Node K,et al.3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors atten-uate vascular smooth muscle prolif-eration by preventing rho GTPase-induced down-regulation of p27Kip1.J Biol Chem,1999,274:2192621931.
- [11]Oda H,Kasisk BL,Donnell MP,et al.Effects of lovastatin on expression of cell cyclin regulatory proteins in vascular smooth muscle cells.Kindey Iint,1999,71(Suppl):S202-S205.
- [12]Rao S,Porter DC,Chen X,et al.Lovastat-in-mediated G1ar-rest is through inhibition of the proteasome,independent of hydroxymethyl glutaryl-CoA reductase.Proc Natl Acad Sci USA,1999,96:77977802.
- [13]Ihling C,Technau K,Gross V,et al.Concordant up regulation of type II-TGF-beta-receptor the cyclin-dependent kinase inhibitor p27and cyclin E in human atherosclerotic tissue:implications for lesion cellularity.Atherosclerosis,1999,144:7-14.
- [14]Yokoyama T,Miyauchi K,Kurata T,et al.Inhibitory efficary of pitavastatin on the early inflammatory response and neointimal thickening in porcine coronary after stenting.Atheroscelrosis,2004,174:253-259.