姜黄素对兔血管球囊损伤后内膜增生的影响
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摘要
经皮腔内冠状动脉血管成形术(PTC A)自1977年应用于临床以来取得了显著的疗效，成为临床治疗冠状动脉疾病的重要手段，但术后3-6月再狭窄发生率高达50-60％，严重影响了该项手术的推广应用。近年来，随着PTCA术后再狭窄机制的研究，认为PTCA术后再狭窄的发生与扩张血管的回缩，亚急性血栓的形成，内皮细胞功能受损，内膜下血管平滑肌细胞的活化，迁延，过度增生及细胞外基质生成有关，与局部炎症反应，细胞因子的作用，癌基因及抑癌基因的过度表达相关。但临床应用抗血栓药物、抗凝药物、血管紧张素转化酶抑制剂、血管紧张素Ⅱ受体拮抗剂、钙通道阻滞剂等均未能抑制术后再狭窄的发生。
晚近报道的药物涂层支架对再狭窄疗效较好，特别是抗癌药物(如Taxol)涂层支架的应用取得了令人鼓舞的效果，但药物涂层支架制作工艺要求较高，价格昂贵，不适合于国情，因此寻找一种能有效防治再狭窄的药物成为国内外冠脉介入治疗研究热点。
姜黄素是从姜科植物姜黄中提取的一种酚类物质，作为食品添加剂已被广泛应用。姜黄素安全性高，几乎无毒，除具有抗氧化，抗感染，抗炎，抗凝，降血脂，抗动脉粥样硬化等药理作用外，还具有抑制血小板聚集，增加纤溶系统活性的作用。对姜黄素抑制体外肿瘤生长的机制研究表明，姜黄素的抗癌作用与诱导肿瘤细胞凋亡密切相关。球囊损伤部位平滑肌细胞过度增殖是血管成形术后再狭窄的重要机制，抑制平滑肌细胞增殖，诱导平滑肌细胞凋亡成为治疗再狭窄
产燕京Z多荞买才笋动里‘笋乙全了旨戈-
的重要途径。细胞凋亡是细胞主动死亡的过程，是具有特征
性的形态和生化改变的由基因调控的个别细胞发生的自主
有序的死亡。P53和Caspase3是较早发现与凋亡相关基因，
可以促进细胞的凋亡。
目前认为再狭窄的主要病理基础是血管平滑肌细胞的
大增殖，其发生与肿瘤发生有相似的分子生物学机制，因此，
保持血管平滑肌增殖与凋亡的平衡就成为防治再狭窄的重
要手段。国内外对姜黄素的上述药理作用研究较多，但将姜
黄素应用于血管内膜损伤后再狭窄的研究尚未见报道。本课
题旨在探讨姜黄素对再狭窄的防治作用及其作用的分子机
制，为临床治疗再狭窄提供实验依据。
目的
1.观察高脂饮食兔骼动脉内皮剥脱后管腔狭窄与平滑
j]L细胞增殖的关系，探讨平滑肌细胞在血管损伤后内膜增生
中的作用。
2.姜黄素在体内对兔骼动脉内皮剥脱后内膜增生是否具
有抑制作用
3姜黄素抑制内膜增生的机制
方法
1.新西兰大白兔30只，体重2.skg士0.25kg，雌雄不限
(购于江苏省农科院)。随机分为3组，对照组(Gl)、阿托
伐他汀组(GZ)、姜黄素组(G3)、每组各10只。各组实验
动物均予6%猪油、1%胆固醇、93%基拙饲料喂养，自由饮水。
采用灌胃给药，剂量如下:姜黄素10腼g/kg/d，阿托伐他汀
2.smg/kg/d，对照组生理盐水5ml/d，一周后，建立骼动脉
内膜球囊损伤模型。喂养5周后，予乌拉糖19/kg麻醉，心
2右京医了买犬学硕若笋应.2旨戈
脏穿刺抽血，检测血脂、SOD、MDA、工L一6。分离剪下右侧骼
动脉，分别行HE染色、We 1 gert弹力纤维染色，MPIAS一500
型图象分析仪分析图象，测量内膜及中膜面积，取长Zmm骼
动脉节段，预固定后行透镜观察细胞微结构。部分标本进行
液氮处理，采用RT一PCR检测ps3、easpase3基因的表达。
结果
1.血脂水平血脂检测结果发现血甘油三脂、胆固醇、
LDL、由高到低为:Gl>GZ>G3。HDL含量:G3>GZ>Gl。姜黄素
和阿托伐他汀钙都可以显著降低兔血清胆固醇和甘油三脂、
LDL含量，HDL在姜黄素组明显高于其他组。G3组与G1组比
较有显著性差异(p<0.01)，具有统计学意义。GZ组与G1组
比较有显著性差异(P<0.01)，有统计学意义。
2.形态学观察内膜增生程度由高到低为:Gl>G2>G3。G3
组与G1组比较差异显著(p<0.05)，具有统计学意义。G2组
与Gl组比较差异显著(p<0.05)，具有统计学意义。电镜观
察姜黄素组平滑肌细胞可见早中期细胞凋亡。
3.氧化应激和炎症指标姜黄素组SOD含量明显高于其
他两组，MDA含量明显低于对照组。IL一6含量由高到低为:
Gl>GZ>G3。G3组与Gl组比较有显著性差异(p<0.0一)，具有
统计学意义。GZ组与G1组比较有显著性差异(P<0 .01)，具
有统计学意义。
4.凋亡基因的检测P53在姜黄素组的表达明显增高，
CasPase3在姜黄素组最高。G3组与G1组比较有极显著差异
(p<0.01)，有统计学意义。GZ组与G1组比较有极显著差异
(p<0.01)，有统计学意义。
夕看万巍墓荞召才李颐士兰笋应.了皆戈r
结论
1.平滑肌细胞增生在骼动脉球囊损伤后的内膜增生起
着重要的作用。
2.姜黄素对高脂饮食的家兔具有调脂、抗炎、抗氧化
作用。能够诱导家兔骼动脉球囊损伤后增生的平滑肌细胞的
调亡。
3.姜黄素减轻骼动脉球囊损伤后的内膜增生，其机制可
能与其调脂、抗炎、抗氧化、诱导血管平滑肌细胞的凋亡等
作用有关。
Effects of curcumin on intima hyperplasia after balloon injury of Rabbit's iliac artery
Although the percutaneous transluminal coronary angioplasty(PTCA) has showed marked effect and been an important means on the treatment of Coronary artery disease since it applied to clinical in 1977, the occurance rate of restenosis within 3 to 6 months after the operation is high to 50%-60%,which limited the application of its clinical.in recent years,with the study on the mechanism of the restenosis,as we all known,the process of restenosis includes.(1) subacute thrombosis formation, (2) inflammatory process , (3) proliferation of VSMC , (4) formation and disposition of extracelluar matrix(ECM) , (5) vessel remodeling. The proliferation and migration of VSMC were studied in the past, the retraction of the expanded vascular,damage of the endotheliums founction,the effect of cytokine,but use drugs of
antithrombo,anticoagulate,angiotensin-con verting enzyme
inhibitor agent blocker of calcium channel, on restenosis has little effect Some report the drug coat stent has gain good effect on the restenosis after PTCA.For example,the taxol coat stent has made inspiriting success,but the fabrication technique of drug coat stent claim high,cost expensive,not match our situation.so it has been a hot spot in the research to find an effective drug after interventional therapy on CAD.
Curcumin ,a phenol extract from a plant,has been widely used as a food additive.it has high reliability,almost has no poison,has the action of
anti-oxidation,anti-infection,anti-inflamation,anti-coagulate,lo w blood lipo,anti-atherosclerosis,and anti-platelet
aggregation,promtes the action of fine dissolve,the study of ccurcumin depress the growth of tumor in vivo or in vitro show that the action of anti-tumor of curcumin has an close correlation with induce the cell apoptosis and
super-proliferation of smooth muscle cell in the spot injury by balloon plays a very importment role in the process of restenosis after PTCA.so depress the proliferation of VSMC,induce the apoptosis of VSMC become an importment means on the treatment of restentosis.Apoptosis is a process of individual cell initiative dead which possess character form and alteration control by gene.p53 and caspase3 are detected early apoptosis gene,which can accelerate the apoptosis. Now it has been found that the prolifer of VSMC has the same molecular biology mechanism as the tumor.So to keep good balance of VSMC prolifer and apoptosis become an importment means on the treatment of restenosis.The report on the action of curcumin above-mentioned are more,but there is no report on the apply curcumin to treatment of restenosis.in this study,we manage to find the treatment of curcumin on restenosis and the moleculor mechanism.provide the base for clinic.
Objective:
1.To Investigate the role of the proliferation of VSMC in process of restenosis.
2 To find Effects of curcumin on intima hyperplasia after balloon injury of Rabbit's iliac artery
3 To find the molecul mechanism.provide the base for clinical.
Methods: 30 New Zealand Rabbits were devided randomly into 3 groups: Control group(G1),Atorvastatin group (G2),Crucumin group(G3). Each group has 10 rabbits. Rabbits in G1,G2,G3 were fed on normal saline,Atorvastatin 2.5mg/kg/d, Cucumin 100mg/kg/d. respectively.Model of ballon injury of iliac artery was established after a week .On the 5th week.blood-lipid,SOD,MDA, IL-6 were examined and the target vessel was taken out. The intima hyperplasia was observed by HE and elastic fibers staining. Cell apoptosis was determined with electron microscopy and apoptosis Gene P53 and Caspase 3 were detected.
Result: The Content of TC, TG, LDL, IL-6 in the blood and the area of neointima from high to low was G1,G2,G3,respectively. The content of HDL from high to low was G3,G2,G1. In G3, The content of SOD apparently higher than the other two, The
晚近报道的药物涂层支架对再狭窄疗效较好，特别是抗癌药物(如Taxol)涂层支架的应用取得了令人鼓舞的效果，但药物涂层支架制作工艺要求较高，价格昂贵，不适合于国情，因此寻找一种能有效防治再狭窄的药物成为国内外冠脉介入治疗研究热点。
姜黄素是从姜科植物姜黄中提取的一种酚类物质，作为食品添加剂已被广泛应用。姜黄素安全性高，几乎无毒，除具有抗氧化，抗感染，抗炎，抗凝，降血脂，抗动脉粥样硬化等药理作用外，还具有抑制血小板聚集，增加纤溶系统活性的作用。对姜黄素抑制体外肿瘤生长的机制研究表明，姜黄素的抗癌作用与诱导肿瘤细胞凋亡密切相关。球囊损伤部位平滑肌细胞过度增殖是血管成形术后再狭窄的重要机制，抑制平滑肌细胞增殖，诱导平滑肌细胞凋亡成为治疗再狭窄
产燕京Z多荞买才笋动里‘笋乙全了旨戈-
的重要途径。细胞凋亡是细胞主动死亡的过程，是具有特征
性的形态和生化改变的由基因调控的个别细胞发生的自主
有序的死亡。P53和Caspase3是较早发现与凋亡相关基因，
可以促进细胞的凋亡。
目前认为再狭窄的主要病理基础是血管平滑肌细胞的
大增殖，其发生与肿瘤发生有相似的分子生物学机制，因此，
保持血管平滑肌增殖与凋亡的平衡就成为防治再狭窄的重
要手段。国内外对姜黄素的上述药理作用研究较多，但将姜
黄素应用于血管内膜损伤后再狭窄的研究尚未见报道。本课
题旨在探讨姜黄素对再狭窄的防治作用及其作用的分子机
制，为临床治疗再狭窄提供实验依据。
目的
1.观察高脂饮食兔骼动脉内皮剥脱后管腔狭窄与平滑
j]L细胞增殖的关系，探讨平滑肌细胞在血管损伤后内膜增生
中的作用。
2.姜黄素在体内对兔骼动脉内皮剥脱后内膜增生是否具
有抑制作用
3姜黄素抑制内膜增生的机制
方法
1.新西兰大白兔30只，体重2.skg士0.25kg，雌雄不限
(购于江苏省农科院)。随机分为3组，对照组(Gl)、阿托
伐他汀组(GZ)、姜黄素组(G3)、每组各10只。各组实验
动物均予6%猪油、1%胆固醇、93%基拙饲料喂养，自由饮水。
采用灌胃给药，剂量如下:姜黄素10腼g/kg/d，阿托伐他汀
2.smg/kg/d，对照组生理盐水5ml/d，一周后，建立骼动脉
内膜球囊损伤模型。喂养5周后，予乌拉糖19/kg麻醉，心
2右京医了买犬学硕若笋应.2旨戈
脏穿刺抽血，检测血脂、SOD、MDA、工L一6。分离剪下右侧骼
动脉，分别行HE染色、We 1 gert弹力纤维染色，MPIAS一500
型图象分析仪分析图象，测量内膜及中膜面积，取长Zmm骼
动脉节段，预固定后行透镜观察细胞微结构。部分标本进行
液氮处理，采用RT一PCR检测ps3、easpase3基因的表达。
结果
1.血脂水平血脂检测结果发现血甘油三脂、胆固醇、
LDL、由高到低为:Gl>GZ>G3。HDL含量:G3>GZ>Gl。姜黄素
和阿托伐他汀钙都可以显著降低兔血清胆固醇和甘油三脂、
LDL含量，HDL在姜黄素组明显高于其他组。G3组与G1组比
较有显著性差异(p<0.01)，具有统计学意义。GZ组与G1组
比较有显著性差异(P<0.01)，有统计学意义。
2.形态学观察内膜增生程度由高到低为:Gl>G2>G3。G3
组与G1组比较差异显著(p<0.05)，具有统计学意义。G2组
与Gl组比较差异显著(p<0.05)，具有统计学意义。电镜观
察姜黄素组平滑肌细胞可见早中期细胞凋亡。
3.氧化应激和炎症指标姜黄素组SOD含量明显高于其
他两组，MDA含量明显低于对照组。IL一6含量由高到低为:
Gl>GZ>G3。G3组与Gl组比较有显著性差异(p<0.0一)，具有
统计学意义。GZ组与G1组比较有显著性差异(P<0 .01)，具
有统计学意义。
4.凋亡基因的检测P53在姜黄素组的表达明显增高，
CasPase3在姜黄素组最高。G3组与G1组比较有极显著差异
(p<0.01)，有统计学意义。GZ组与G1组比较有极显著差异
(p<0.01)，有统计学意义。
夕看万巍墓荞召才李颐士兰笋应.了皆戈r
结论
1.平滑肌细胞增生在骼动脉球囊损伤后的内膜增生起
着重要的作用。
2.姜黄素对高脂饮食的家兔具有调脂、抗炎、抗氧化
作用。能够诱导家兔骼动脉球囊损伤后增生的平滑肌细胞的
调亡。
3.姜黄素减轻骼动脉球囊损伤后的内膜增生，其机制可
能与其调脂、抗炎、抗氧化、诱导血管平滑肌细胞的凋亡等
作用有关。
Effects of curcumin on intima hyperplasia after balloon injury of Rabbit's iliac artery
Although the percutaneous transluminal coronary angioplasty(PTCA) has showed marked effect and been an important means on the treatment of Coronary artery disease since it applied to clinical in 1977, the occurance rate of restenosis within 3 to 6 months after the operation is high to 50%-60%,which limited the application of its clinical.in recent years,with the study on the mechanism of the restenosis,as we all known,the process of restenosis includes.(1) subacute thrombosis formation, (2) inflammatory process , (3) proliferation of VSMC , (4) formation and disposition of extracelluar matrix(ECM) , (5) vessel remodeling. The proliferation and migration of VSMC were studied in the past, the retraction of the expanded vascular,damage of the endotheliums founction,the effect of cytokine,but use drugs of
antithrombo,anticoagulate,angiotensin-con verting enzyme
inhibitor agent blocker of calcium channel, on restenosis has little effect Some report the drug coat stent has gain good effect on the restenosis after PTCA.For example,the taxol coat stent has made inspiriting success,but the fabrication technique of drug coat stent claim high,cost expensive,not match our situation.so it has been a hot spot in the research to find an effective drug after interventional therapy on CAD.
Curcumin ,a phenol extract from a plant,has been widely used as a food additive.it has high reliability,almost has no poison,has the action of
anti-oxidation,anti-infection,anti-inflamation,anti-coagulate,lo w blood lipo,anti-atherosclerosis,and anti-platelet
aggregation,promtes the action of fine dissolve,the study of ccurcumin depress the growth of tumor in vivo or in vitro show that the action of anti-tumor of curcumin has an close correlation with induce the cell apoptosis and
super-proliferation of smooth muscle cell in the spot injury by balloon plays a very importment role in the process of restenosis after PTCA.so depress the proliferation of VSMC,induce the apoptosis of VSMC become an importment means on the treatment of restentosis.Apoptosis is a process of individual cell initiative dead which possess character form and alteration control by gene.p53 and caspase3 are detected early apoptosis gene,which can accelerate the apoptosis. Now it has been found that the prolifer of VSMC has the same molecular biology mechanism as the tumor.So to keep good balance of VSMC prolifer and apoptosis become an importment means on the treatment of restenosis.The report on the action of curcumin above-mentioned are more,but there is no report on the apply curcumin to treatment of restenosis.in this study,we manage to find the treatment of curcumin on restenosis and the moleculor mechanism.provide the base for clinic.
Objective:
1.To Investigate the role of the proliferation of VSMC in process of restenosis.
2 To find Effects of curcumin on intima hyperplasia after balloon injury of Rabbit's iliac artery
3 To find the molecul mechanism.provide the base for clinical.
Methods: 30 New Zealand Rabbits were devided randomly into 3 groups: Control group(G1),Atorvastatin group (G2),Crucumin group(G3). Each group has 10 rabbits. Rabbits in G1,G2,G3 were fed on normal saline,Atorvastatin 2.5mg/kg/d, Cucumin 100mg/kg/d. respectively.Model of ballon injury of iliac artery was established after a week .On the 5th week.blood-lipid,SOD,MDA, IL-6 were examined and the target vessel was taken out. The intima hyperplasia was observed by HE and elastic fibers staining. Cell apoptosis was determined with electron microscopy and apoptosis Gene P53 and Caspase 3 were detected.
Result: The Content of TC, TG, LDL, IL-6 in the blood and the area of neointima from high to low was G1,G2,G3,respectively. The content of HDL from high to low was G3,G2,G1. In G3, The content of SOD apparently higher than the other two, The
引文
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2 Block PC, Banghman KI,Pasterank RC,et al.Transluminar angioplasty:correlation of morphologic and angiographic findings in an experimental model. Circulation,1980;61:778
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8. Jorgensen B,Simonsen S,Endresen K,et al.Restenosis and clinical outcome in patients treated with Amlodipine after angioplasty:results from CAPARES.Am Coll Cardiol,2000; 35(3):592-599
9. Tulenko TN,Brown J,Laury-Kleintop L,et al.Atheroprotection with amiodipine:cells to lesions and the PREVENT trial[J].J Cardiovasc Parmacol,1999; 33(suppl 2):S17-S22
10. Eickeiberg O,Roth M,Block LH.Effects of amlodipine on geme expression and extracellular matrix formation in human vascular smooth muscle cells and fibroblasts:implication for vascular protection.Int J Cardiol,1997; 62(suppl 2):S31-S37
11. Watanabe K,Sekiya M,Ikeda S,et al.Prevention effects of probucol on restenosis after percutaneous transluminal coronary angioplasty.Am Heart J,1996; 132(1 pt 1):23
12. Tarif JC,Cote G,Lesperance J,et al.Probucol and multivitamins in the prevention of restenosis after coronary angioplasty.N Engl J Med, 1997; 337(6): 365
13. Sharma AC,Motev SJ,Farias S.Sepsis alters myocardial and plasma concentrations of endotheline and nitric oxide in rats.J Moll Cell Cardiol,1997; 29(5):1469
14. Mckenna CH,Burke S,Opgenorth T,et al.Selective ET_A receptor antagonism reduces neointrmal hyperplasia in a porcine coronary stent model.Circulation, 1998; 97(25):2551-2556
15. Havdhammar PA,van Beusekom HM,Emanuelsson HU,et
al.Reduction in thrimbitic events with heparin-coated Palmaz-schatz stent in normal porcine coronary artery.Circulation, 1996; 93(3):423-430
16. De Scheerder I,Wang K,Wilczek K,et al.Experimental study of thrombogenicity and foreign body reaction induced by heparin-coated coronar stents.Circulation, 1997; 95(6):1549-1553
17. Gao RL,Yuan JQ,shi RW,et al.Intracoronary prourokinase gene transfer with protein-coated stent decreased platelet deposition and smooth muscle cell proliferation in mini-swine.JACC,1998; 31:5(suppl C):257C
18. Gao RL,Yuan JQ,Shi RW,et al.Intravascular local gene transfer mediated by protein-coated metallic stent.JACC,1998; 31:5(suppl C):203C
19. Yang Zy,Simari RD,Perkins ND,et al.Role of the P21 cyclin-dependent kinase in limiting intimal cell proliferation in response to arterial injury.Proc Natl Acad sci USA,1996; 93(15):7905-7910
20 Gotto Jr AM, Larosa JC, Hunninghake D, et al. AHA Medical/scientific statement.The cholesterol facts: a summary of the evidence relating dietarty fats, serum cholesterol, and coronary heart disease. Circulation, 1990,81: 1721-1725.
21 Fleishen LN, Tal AR, Witte LD, et al. Stimulation of arterial endothelial prostacyclin synthesis by high density lipoproteins. J Biol Chem, 1982, 257(12): 6653-6662.
22 Muller DWM, Ellis SG, Topol EJ. Experimental models of coronary artery restenosis. JACC,1990: 19(2), 418-422.
23 Nunes GL,sgoutas DS,Redden RA,et al.Combination of vitamins C and E alters the response to coronary balloon injury in the pig[J].Arterioscler Thromb Vasc Biol.1995,5(1):156～158
24 贾亚峰，血脂失调和动脉粥样硬化治疗的现状与进展，国外医学药学分册。2002，28(4)：209-213
25 Guarda E, Katwa LC, Campbell SE, et al. extracellular matrix collagen Synthesis and degradation following coronary balloon angioplasty. J Mol Cell Cardiol, 1996,28: 699-706.
26 Xi XP, Graf K, Goelze S, et al. Central role of the MAPK pathway in Ang Ⅱ mediated DNA synthesis and migration in rat vascular smooth muscle cells. Arterioscler Thromb Vasc Biol, 1999,19: 73.
27 沃兴德，洪行球，赵革平等．姜黄素对低密度脂蛋白和脂蛋白(a)代谢的影响．中国动脉硬化杂志，1999；7(4)：339-341
28 沃兴德，金明敏．姜黄对高胆固醇和高脂肪膳食小鼠脂代谢的影响．浙江中医学院学报，1998；22(6)
29 Zhang WL,Liu DW,Wo XD,et al.Effects of Cucurma longa on proliferation of cultured bovine smooth muscle cells and on expression of low density lipoprotein receptor in cells. Chin Med J,1999; 112(4): 308-311
30 王舒然．姜黄素对大鼠调节血脂及抗氧化作用的研究．卫生研究，2000；29(4)：240—242
31 Smonina NA, Coyle JT. [J]. Annu Rev Pharmacol Toxicol, 1996, 36: 83-106
32 夏敏，氧化应激与动脉粥样硬化。国外医学内科学分册，
2001, 28(8): 323-326
33 张玉锦，洪小茜。活性氧与心血管疾病关系的研究。2002，8(4)：212-213
34 Palinski W,Tangirala RK,Miller E,et al. 「J」. Arterioscler Thromb Vasc Biol,1995,15:1569-1576
35 Steinberg D. 「J」.J Biol chem.,1997,272(34):20963-20966
36 Griending KK,Sorescu D,UshioFukai M. 「J」. Circres,2000,86:494-501.
37 Ramos MA,Kuzuya M,Esaki T,et al. 「J」. Arterioscler Thromb Vasc Biol,1998,18(7):1188-1196.
38 Korutla L,Cheung JY,Mendelsohn J,Kumar R.Inhibition of ligand-induced activation of epidermal growth factor receptor tyrosine phosphorylation by curcumin.Carcinogenesis, 1995; 16(8): 1741-5
39 Caillaud C,Py G,Eydous N,et al. 「J」. Free Radic Biol Med,1999,26(9-10):1292-1299
40 石晶，顾军，邓心新等．姜黄素对大鼠心肌缺血性损伤的保护作用，中国药理学通报，1998；14(2)：145—147
41 Lin JK,Shih CA.Inhibitory effect of curcumin on xanthine dehydrogenase/oxidase induced by phorbol-12-myristate-13-acetate in NIH 3T3 cells.Carcinogenesis, 1994; 15(8): 1717—1721
42 Reddy-AC,Lokesh-BR.Effect of Curcumin and eugenol on iron-induced hepatic toxicity in rats.Toxicology,1996;107(1):39
43 Han Dk,Haudenschild CC,Hong MK,et al.Evidence for
apoptosis in human atherogenesis and in a rat vascular injury model.Am J Pathol,1995,147(2):267
44 Kockx MM,Knaapen MW.The role of apoptosis in vascular disease.J Pathol,2000,190(3):267
45 Bochaton Piallat ML,Gabbiani F,Redard M,et al.Apoptosis participates in cellularity regulation during rat aortic intimal thickening.Am J Pathol,1995,146(5):1059
46 Cho A,Courtman DW,Langile BL.Apoptosis in arterics of the neonatl lamb.Circ Res, 1995,76()2:168
47 Kockx MM,Herman AG.Apoptosis in atherogenesis: implications ofor plaque destabilization.Eur Heart J,1998,19(suppl):23
48 Wang BY,Ho HKV,Lin PS,et al.Regression of atherosclerosis: Role of nitric oxide and apoptosis 「J」. Circulation, 1999,99:1236
49 Ross R.Cell biology of atherosclerosis 「J」. Annu Rev Physiol,1995,57:791
50. Rajakumar-DV,Rao-MN.Antioxidant properties of dehydrozingerone and Curcumin in rat brain homogenates.Mol Cell Biochem, 1994;140(1):73
51 许实波．姜黄素的药理作用研究概况．中草药，1991：22(8)：146
52 Rao C V,Rivenson A,Simi B,et al.Chem oprevention of colon carcinogenesis by dietary curcuin,a Naturally Occurring plantphenoloc compound. Cancer Res, 1995; 55: 259
53. mtrakul P,Lipigorngoson S,Namwong O,et al.Inhibitory
effect of diretary curcumin on skin carcinogenesis in mice. Cancer lett, 1997; 116:197
54 许建华，赵蓉，柯丹如．姜黄素的体外抗癌作用及其水溶液的稳定性．中国药理学通报，1998；14(5)：415—417
55．许建华，赵蓉，吴国士．姜黄素的抗肿瘤作用．中药药理与临床，1998；14(3)：15—17
56 张立实，张建清，王怡净．用基因突变试验评价姜黄素的抗诱变性．癌变·畸变·突变，1999；11(6)：311—312
57 陈宏，张振书，张亚历等．姜黄素诱导Lovo细胞凋亡．中国中医基础医学杂志，1999；5(3)：32-34
58 Liu JY,Lin S J,L in JK.Inhitibory effects of curcumin in on protein kinase C activity induced by 12-O-tetradecanoylphorbol-13-acetate in NIH 3T3 cells.Carcinogenesis,1993;5:857
59 吴裕丹，陈燕，何明生等．姜黄素对细胞周期的影响及对比研究．现代临床医学生物工程学杂志，1999；5(3)：177
60 Klampfer L,Cammenga J,Wisniewski H G.et al.Sodium salicylate activates caspases and induses apoptosis of myeloid leukemia cell lines.Blood,1999;93:2386
61 ufmann SH,Karp J E,Svingen P A et al.Elevated expression of the apoptotic regulator Mcl-1 at the time of leukemic relapse.Blood, 1998;91:991
62 Dreher D,Junod AF.Role of oxygen free radicals in cancer development.Eur J Cancer, 1996;32A(1):30-38
63 Joe-B,Lokesh-BR.Role of capsaicin,curcumin and dietary
n-3fatty acids in lowering the generation of reactive oxygen species in rtperitoneal macrophages.Biochim Biophys Acta, 1994; 1224(2): 255
64 蒋德昭，谢祁阳，王如．姜黄素对小鼠CFU-GM及WEHI-3B细胞增殖的影响．湖南医科大学学报，2000；25(3)：216—218
2 Block PC, Banghman KI,Pasterank RC,et al.Transluminar angioplasty:correlation of morphologic and angiographic findings in an experimental model. Circulation,1980;61:778
3．龙明智，黄峻．PTCA术后再狭窄机理研究及其防治进展[J]．心血管病学进展，2001；22(6)：326～329
4 Tcheng JE.Glycoprotein Ⅱb/Ⅲa receptor inhibitors:putting the EPIC IMPACT Ⅱ,RESTORE and PEILOG trails into perspective.Am J Cardiol,1996; 78(3A): 35～40
5 Randomized placebo-controlled trail of effect of eptifibatide on complications of percutaneous coronary intervention:IMPACT-Ⅱ.Integrilin to Minimize platelet Aggregation and Coronary Thrombosis-Ⅱ. Lancet, 1997; 349(9063):1422-1428
6 Treasure CB,Klein JL,Weintraub WS,et al.Benifical effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary arterydisease.NEJM,1995; 332(8):481-487
7 Jukema JW,Bruschke AVG,van Broven AJ,et al.ON behalf to the REGRESS study group,Inter University Cardiology Institute Utrecht,the Netherlands.Effects of Lipid Loweringby pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serm cholesterol levels. The Regression
Growth Evaluation Statin Study(REGRESS).Circulation, 1995; 91(10):2528-540
8. Jorgensen B,Simonsen S,Endresen K,et al.Restenosis and clinical outcome in patients treated with Amlodipine after angioplasty:results from CAPARES.Am Coll Cardiol,2000; 35(3):592-599
9. Tulenko TN,Brown J,Laury-Kleintop L,et al.Atheroprotection with amiodipine:cells to lesions and the PREVENT trial[J].J Cardiovasc Parmacol,1999; 33(suppl 2):S17-S22
10. Eickeiberg O,Roth M,Block LH.Effects of amlodipine on geme expression and extracellular matrix formation in human vascular smooth muscle cells and fibroblasts:implication for vascular protection.Int J Cardiol,1997; 62(suppl 2):S31-S37
11. Watanabe K,Sekiya M,Ikeda S,et al.Prevention effects of probucol on restenosis after percutaneous transluminal coronary angioplasty.Am Heart J,1996; 132(1 pt 1):23
12. Tarif JC,Cote G,Lesperance J,et al.Probucol and multivitamins in the prevention of restenosis after coronary angioplasty.N Engl J Med, 1997; 337(6): 365
13. Sharma AC,Motev SJ,Farias S.Sepsis alters myocardial and plasma concentrations of endotheline and nitric oxide in rats.J Moll Cell Cardiol,1997; 29(5):1469
14. Mckenna CH,Burke S,Opgenorth T,et al.Selective ET_A receptor antagonism reduces neointrmal hyperplasia in a porcine coronary stent model.Circulation, 1998; 97(25):2551-2556
15. Havdhammar PA,van Beusekom HM,Emanuelsson HU,et
al.Reduction in thrimbitic events with heparin-coated Palmaz-schatz stent in normal porcine coronary artery.Circulation, 1996; 93(3):423-430
16. De Scheerder I,Wang K,Wilczek K,et al.Experimental study of thrombogenicity and foreign body reaction induced by heparin-coated coronar stents.Circulation, 1997; 95(6):1549-1553
17. Gao RL,Yuan JQ,shi RW,et al.Intracoronary prourokinase gene transfer with protein-coated stent decreased platelet deposition and smooth muscle cell proliferation in mini-swine.JACC,1998; 31:5(suppl C):257C
18. Gao RL,Yuan JQ,Shi RW,et al.Intravascular local gene transfer mediated by protein-coated metallic stent.JACC,1998; 31:5(suppl C):203C
19. Yang Zy,Simari RD,Perkins ND,et al.Role of the P21 cyclin-dependent kinase in limiting intimal cell proliferation in response to arterial injury.Proc Natl Acad sci USA,1996; 93(15):7905-7910
20 Gotto Jr AM, Larosa JC, Hunninghake D, et al. AHA Medical/scientific statement.The cholesterol facts: a summary of the evidence relating dietarty fats, serum cholesterol, and coronary heart disease. Circulation, 1990,81: 1721-1725.
21 Fleishen LN, Tal AR, Witte LD, et al. Stimulation of arterial endothelial prostacyclin synthesis by high density lipoproteins. J Biol Chem, 1982, 257(12): 6653-6662.
22 Muller DWM, Ellis SG, Topol EJ. Experimental models of coronary artery restenosis. JACC,1990: 19(2), 418-422.
23 Nunes GL,sgoutas DS,Redden RA,et al.Combination of vitamins C and E alters the response to coronary balloon injury in the pig[J].Arterioscler Thromb Vasc Biol.1995,5(1):156～158
24 贾亚峰，血脂失调和动脉粥样硬化治疗的现状与进展，国外医学药学分册。2002，28(4)：209-213
25 Guarda E, Katwa LC, Campbell SE, et al. extracellular matrix collagen Synthesis and degradation following coronary balloon angioplasty. J Mol Cell Cardiol, 1996,28: 699-706.
26 Xi XP, Graf K, Goelze S, et al. Central role of the MAPK pathway in Ang Ⅱ mediated DNA synthesis and migration in rat vascular smooth muscle cells. Arterioscler Thromb Vasc Biol, 1999,19: 73.
27 沃兴德，洪行球，赵革平等．姜黄素对低密度脂蛋白和脂蛋白(a)代谢的影响．中国动脉硬化杂志，1999；7(4)：339-341
28 沃兴德，金明敏．姜黄对高胆固醇和高脂肪膳食小鼠脂代谢的影响．浙江中医学院学报，1998；22(6)
29 Zhang WL,Liu DW,Wo XD,et al.Effects of Cucurma longa on proliferation of cultured bovine smooth muscle cells and on expression of low density lipoprotein receptor in cells. Chin Med J,1999; 112(4): 308-311
30 王舒然．姜黄素对大鼠调节血脂及抗氧化作用的研究．卫生研究，2000；29(4)：240—242
31 Smonina NA, Coyle JT. [J]. Annu Rev Pharmacol Toxicol, 1996, 36: 83-106
32 夏敏，氧化应激与动脉粥样硬化。国外医学内科学分册，
2001, 28(8): 323-326
33 张玉锦，洪小茜。活性氧与心血管疾病关系的研究。2002，8(4)：212-213
34 Palinski W,Tangirala RK,Miller E,et al. 「J」. Arterioscler Thromb Vasc Biol,1995,15:1569-1576
35 Steinberg D. 「J」.J Biol chem.,1997,272(34):20963-20966
36 Griending KK,Sorescu D,UshioFukai M. 「J」. Circres,2000,86:494-501.
37 Ramos MA,Kuzuya M,Esaki T,et al. 「J」. Arterioscler Thromb Vasc Biol,1998,18(7):1188-1196.
38 Korutla L,Cheung JY,Mendelsohn J,Kumar R.Inhibition of ligand-induced activation of epidermal growth factor receptor tyrosine phosphorylation by curcumin.Carcinogenesis, 1995; 16(8): 1741-5
39 Caillaud C,Py G,Eydous N,et al. 「J」. Free Radic Biol Med,1999,26(9-10):1292-1299
40 石晶，顾军，邓心新等．姜黄素对大鼠心肌缺血性损伤的保护作用，中国药理学通报，1998；14(2)：145—147
41 Lin JK,Shih CA.Inhibitory effect of curcumin on xanthine dehydrogenase/oxidase induced by phorbol-12-myristate-13-acetate in NIH 3T3 cells.Carcinogenesis, 1994; 15(8): 1717—1721
42 Reddy-AC,Lokesh-BR.Effect of Curcumin and eugenol on iron-induced hepatic toxicity in rats.Toxicology,1996;107(1):39
43 Han Dk,Haudenschild CC,Hong MK,et al.Evidence for
apoptosis in human atherogenesis and in a rat vascular injury model.Am J Pathol,1995,147(2):267
44 Kockx MM,Knaapen MW.The role of apoptosis in vascular disease.J Pathol,2000,190(3):267
45 Bochaton Piallat ML,Gabbiani F,Redard M,et al.Apoptosis participates in cellularity regulation during rat aortic intimal thickening.Am J Pathol,1995,146(5):1059
46 Cho A,Courtman DW,Langile BL.Apoptosis in arterics of the neonatl lamb.Circ Res, 1995,76()2:168
47 Kockx MM,Herman AG.Apoptosis in atherogenesis: implications ofor plaque destabilization.Eur Heart J,1998,19(suppl):23
48 Wang BY,Ho HKV,Lin PS,et al.Regression of atherosclerosis: Role of nitric oxide and apoptosis 「J」. Circulation, 1999,99:1236
49 Ross R.Cell biology of atherosclerosis 「J」. Annu Rev Physiol,1995,57:791
50. Rajakumar-DV,Rao-MN.Antioxidant properties of dehydrozingerone and Curcumin in rat brain homogenates.Mol Cell Biochem, 1994;140(1):73
51 许实波．姜黄素的药理作用研究概况．中草药，1991：22(8)：146
52 Rao C V,Rivenson A,Simi B,et al.Chem oprevention of colon carcinogenesis by dietary curcuin,a Naturally Occurring plantphenoloc compound. Cancer Res, 1995; 55: 259
53. mtrakul P,Lipigorngoson S,Namwong O,et al.Inhibitory
effect of diretary curcumin on skin carcinogenesis in mice. Cancer lett, 1997; 116:197
54 许建华，赵蓉，柯丹如．姜黄素的体外抗癌作用及其水溶液的稳定性．中国药理学通报，1998；14(5)：415—417
55．许建华，赵蓉，吴国士．姜黄素的抗肿瘤作用．中药药理与临床，1998；14(3)：15—17
56 张立实，张建清，王怡净．用基因突变试验评价姜黄素的抗诱变性．癌变·畸变·突变，1999；11(6)：311—312
57 陈宏，张振书，张亚历等．姜黄素诱导Lovo细胞凋亡．中国中医基础医学杂志，1999；5(3)：32-34
58 Liu JY,Lin S J,L in JK.Inhitibory effects of curcumin in on protein kinase C activity induced by 12-O-tetradecanoylphorbol-13-acetate in NIH 3T3 cells.Carcinogenesis,1993;5:857
59 吴裕丹，陈燕，何明生等．姜黄素对细胞周期的影响及对比研究．现代临床医学生物工程学杂志，1999；5(3)：177
60 Klampfer L,Cammenga J,Wisniewski H G.et al.Sodium salicylate activates caspases and induses apoptosis of myeloid leukemia cell lines.Blood,1999;93:2386
61 ufmann SH,Karp J E,Svingen P A et al.Elevated expression of the apoptotic regulator Mcl-1 at the time of leukemic relapse.Blood, 1998;91:991
62 Dreher D,Junod AF.Role of oxygen free radicals in cancer development.Eur J Cancer, 1996;32A(1):30-38
63 Joe-B,Lokesh-BR.Role of capsaicin,curcumin and dietary
n-3fatty acids in lowering the generation of reactive oxygen species in rtperitoneal macrophages.Biochim Biophys Acta, 1994; 1224(2): 255
64 蒋德昭，谢祁阳，王如．姜黄素对小鼠CFU-GM及WEHI-3B细胞增殖的影响．湖南医科大学学报，2000；25(3)：216—218