肿瘤抑制因子基因转染兔抑制血管再狭窄的实验研究
摘要
近年来,随着介入性心脏病学的迅速发展和广泛应用,经皮冠状动脉介入术(PCI)已在我国许多医院开展起来,这是值得可喜的。但是PCI后的主要长期并发症——冠状动脉再狭窄发生率较高,这也是目前开展冠心病(CHD)介入性治疗的主要障碍,严重地影响了PCI的长期疗效。在PCI术后再狭窄的形成机制中,“血管平滑肌细胞(vascular smooth muscle cells, VSMC)的增殖及迁移学说”占有重要地位。药物治疗再狭窄的方法不是完全令人满意,所以积极探求防治再狭窄的新途径显得尤为重要。自90年代开始,一种新的治疗技术即基因治疗出现了,为人类研究现代治疗学开辟了新的道路。本研究的目的是通过对动脉平滑肌细胞进行体内、外实验转染PTEN基因,观察其对PDGF诱导的VSMC增殖(MTT)与信号传导通路的影响,以及对内皮损伤后内膜增生的影响,从而了解PTEN在防治再狭窄过程中的作用,以期得到更好的治疗方法。
本实验成功构建了pcDNA4/myc-His-PTEN真核表达质粒,脂质体介导转染VSMC细胞,重组hPTEN基因修饰可抑制PDGF诱导的VSMC增殖；继而通过脂质体介导动脉腔内转染的方式证实PTEN对再狭窄有防治作用。
本研究的创新性在于通过细胞实验及动物实验验证了PTEN可以抑制再狭窄。
1 Objective:
Nearly, percutaneous transluminal coronary intervention (PCI) has been developed in many hospitals in China with rapid development and wide apply of intervention cardiopathy. But coronary artery restenosis, that is major lasting combination, happens frequently. It is major obstacle in intervention treatment of coronary heart disease and affects lasting curative effect badly.In the form mechanism of restenosis after PCI, the theory of vascular smooth muscle cells(VSMC) proliferating and moving is very important. Drug therapy for RS is not satisfactory. Toxicity of medicine restricts its clinical application. Therefore it is very imperative to find new ways to control RS.Since 1990s a new technique has been born.that is gene therapy, opening up a new years of modern therapy.
PTEN gene is a new gene gained by Li etal in 1997, and its 175 amino acid sequence is in common with cell franework albumen(tensin).The gene is named by cell tensility albumen, phosphorate enzyme gene deleted on chromosome 10. The gene could induce cell cycle block by regulating PI3K/Akt signal transfer approach, and regulating cell cycle evolvment and cell survival. It could induce cell death and restrain tumor metastasis by affecting FAK and MAPK bypass. It could restrain vascular formation. The level of mRNA of vascular endothelium growth factor(VEGF) was reduced by activated LY294002(the inhibitor of PI3K), what hints that PI3K is very important on vascular formation and regulation of VEGF expression. It is reported that PTEN could regulate a number of signals in correlative with proliferation and restrain cell to span G-S point.Over express of PTEN restrained the reaction of VSMC that appeared key funtion on internal proferation and restenosis. It has been valid method of preventing and curing many vascular diseases including restenosis.In the same time, PTEN appeared negative control on cell spliting and moving. Koide reported that these effctions might due to restraining inflammation reaction, including restraining the incursion of macrophage cell and the express of inflammation cell factor.
Currently, the research is limited on the role of PTEN in RS. Scholars only observed the role of PTEN in RS morphologic cases. The role of PTEN in correlation index and process mechanism of RS has not been reported. Accordingly, firstly PTEN eukaryotic expression vector is constructed in our experiment. In vitro studies, we observed the proliferation induced by PDGF conditioned medium is inhibited on PTEN gene-modified VSMC cells. In vivo studies, We also observed PTEN transfered by artery cavity injection restrains RS in model rabbits.
2 content
First PTEN gene were cloned from pGEM-T-PTEN plasmid into the eukaryotic expression vector pcDNA4/myc-His, recombinant plasmid pcDNA4/myc-His-PTEN was constructed. The truth of gene was tested by application digestion and DNA sequencing. VSMC cells were transfered with pcDNA4/myc-His-PTEN eukaryotic expression vector by Liposome. After G418 selection, MTT assay observed transfected VSMC proliferation induced in human PDGF conditioned medium. Then the gene expression of RS model rabbit was detected in the arteries by injection into the artery cavity, and the the restraining role to RS was studied.
The results show that we constructed the eukaryotic expression vector pcDNA4/myc-His-PTEN successfully. By identifing and sequencing the plasmid we found PTEN was same as the presence of the gene sequence in Genebank. PTEN was transfered into VSMC cells by liposome and expressed stable protein, which could be suggested through RT-PCR and Western blot techniques. The proliferation of VSMC cells induced by PDGF conditioned medium could be inhibited after transfection through MTT assay.On the other hand,in vivo Liposome-induced pcDNA4/myc-His-PTEN could be expressed stably by injecting in rabbits' artery cavity, and inhibited new intermal form significantly also.
3 Major achievements
(1)Internal and external we observed the proliferation of human VSMC cells in PDGF conditioned medium after PTEN gene was transferred into cells by liposome first experim-entally,and we observed the changes of its signal transfection bypass. In conclusion PTEN could inhibit VSMC cell proliferation in this condition.
(2)Internal and external we observed the eukaryotic expression vector pcDNA4/myc-His-PTEN was injected into rabbits'artery cavity by liposome and expressed stable protein in the arteries, at the same time the compound could inhibit RS significantly first experim-entally
4 Significance and value of the research achievements:
Since 1997 PTEN gene was found, a great deal of research has been done by scholars. As a endogenous tumor inhibition factor PTEN has good histocompatibility and could resist angiogenesis significantly. Internal and external it was reported that PTEN gene can be transferred to the target cells by virus vector, or the compound AV-PTEN could be injected into artery cavity in vivo,and the results suggested that PTEN protein content increased in arteries obviously, and in vivo could survival more time to devote treatment effect, had broad prospects for the future.
Although detecting morphological changes in RS cases found PTEN could inhibit new internal form, it was not explicit about the mechanism of PTEN in RS and it was not reported about appropriate research study. We tested PTEN could inhibit VSMC cell proliferation induced with PDGF conditioned media first experimentally, that was due to the gene translation and express of Akt/NF-κB signal convey bypass partly. And PTEN gene was transferred in arteries could also inhibit RS significantly. So this reseach laid a foundation for further study about PTEN roles in RS and its application in the RS prevention.
本实验成功构建了pcDNA4/myc-His-PTEN真核表达质粒,脂质体介导转染VSMC细胞,重组hPTEN基因修饰可抑制PDGF诱导的VSMC增殖；继而通过脂质体介导动脉腔内转染的方式证实PTEN对再狭窄有防治作用。
本研究的创新性在于通过细胞实验及动物实验验证了PTEN可以抑制再狭窄。
1 Objective:
Nearly, percutaneous transluminal coronary intervention (PCI) has been developed in many hospitals in China with rapid development and wide apply of intervention cardiopathy. But coronary artery restenosis, that is major lasting combination, happens frequently. It is major obstacle in intervention treatment of coronary heart disease and affects lasting curative effect badly.In the form mechanism of restenosis after PCI, the theory of vascular smooth muscle cells(VSMC) proliferating and moving is very important. Drug therapy for RS is not satisfactory. Toxicity of medicine restricts its clinical application. Therefore it is very imperative to find new ways to control RS.Since 1990s a new technique has been born.that is gene therapy, opening up a new years of modern therapy.
PTEN gene is a new gene gained by Li etal in 1997, and its 175 amino acid sequence is in common with cell franework albumen(tensin).The gene is named by cell tensility albumen, phosphorate enzyme gene deleted on chromosome 10. The gene could induce cell cycle block by regulating PI3K/Akt signal transfer approach, and regulating cell cycle evolvment and cell survival. It could induce cell death and restrain tumor metastasis by affecting FAK and MAPK bypass. It could restrain vascular formation. The level of mRNA of vascular endothelium growth factor(VEGF) was reduced by activated LY294002(the inhibitor of PI3K), what hints that PI3K is very important on vascular formation and regulation of VEGF expression. It is reported that PTEN could regulate a number of signals in correlative with proliferation and restrain cell to span G-S point.Over express of PTEN restrained the reaction of VSMC that appeared key funtion on internal proferation and restenosis. It has been valid method of preventing and curing many vascular diseases including restenosis.In the same time, PTEN appeared negative control on cell spliting and moving. Koide reported that these effctions might due to restraining inflammation reaction, including restraining the incursion of macrophage cell and the express of inflammation cell factor.
Currently, the research is limited on the role of PTEN in RS. Scholars only observed the role of PTEN in RS morphologic cases. The role of PTEN in correlation index and process mechanism of RS has not been reported. Accordingly, firstly PTEN eukaryotic expression vector is constructed in our experiment. In vitro studies, we observed the proliferation induced by PDGF conditioned medium is inhibited on PTEN gene-modified VSMC cells. In vivo studies, We also observed PTEN transfered by artery cavity injection restrains RS in model rabbits.
2 content
First PTEN gene were cloned from pGEM-T-PTEN plasmid into the eukaryotic expression vector pcDNA4/myc-His, recombinant plasmid pcDNA4/myc-His-PTEN was constructed. The truth of gene was tested by application digestion and DNA sequencing. VSMC cells were transfered with pcDNA4/myc-His-PTEN eukaryotic expression vector by Liposome. After G418 selection, MTT assay observed transfected VSMC proliferation induced in human PDGF conditioned medium. Then the gene expression of RS model rabbit was detected in the arteries by injection into the artery cavity, and the the restraining role to RS was studied.
The results show that we constructed the eukaryotic expression vector pcDNA4/myc-His-PTEN successfully. By identifing and sequencing the plasmid we found PTEN was same as the presence of the gene sequence in Genebank. PTEN was transfered into VSMC cells by liposome and expressed stable protein, which could be suggested through RT-PCR and Western blot techniques. The proliferation of VSMC cells induced by PDGF conditioned medium could be inhibited after transfection through MTT assay.On the other hand,in vivo Liposome-induced pcDNA4/myc-His-PTEN could be expressed stably by injecting in rabbits' artery cavity, and inhibited new intermal form significantly also.
3 Major achievements
(1)Internal and external we observed the proliferation of human VSMC cells in PDGF conditioned medium after PTEN gene was transferred into cells by liposome first experim-entally,and we observed the changes of its signal transfection bypass. In conclusion PTEN could inhibit VSMC cell proliferation in this condition.
(2)Internal and external we observed the eukaryotic expression vector pcDNA4/myc-His-PTEN was injected into rabbits'artery cavity by liposome and expressed stable protein in the arteries, at the same time the compound could inhibit RS significantly first experim-entally
4 Significance and value of the research achievements:
Since 1997 PTEN gene was found, a great deal of research has been done by scholars. As a endogenous tumor inhibition factor PTEN has good histocompatibility and could resist angiogenesis significantly. Internal and external it was reported that PTEN gene can be transferred to the target cells by virus vector, or the compound AV-PTEN could be injected into artery cavity in vivo,and the results suggested that PTEN protein content increased in arteries obviously, and in vivo could survival more time to devote treatment effect, had broad prospects for the future.
Although detecting morphological changes in RS cases found PTEN could inhibit new internal form, it was not explicit about the mechanism of PTEN in RS and it was not reported about appropriate research study. We tested PTEN could inhibit VSMC cell proliferation induced with PDGF conditioned media first experimentally, that was due to the gene translation and express of Akt/NF-κB signal convey bypass partly. And PTEN gene was transferred in arteries could also inhibit RS significantly. So this reseach laid a foundation for further study about PTEN roles in RS and its application in the RS prevention.
引文
[I]Simpson L, Parsons R.PTEN:Life as a tumor suppressor.Exp Cell Res.2001,264(1): 29-36.
[2]Yamada KM, Araki M.Tumor suppressor PTEN:modulator of cell singaling, growth, migration and apoptosis.J Cell Sci,2001,114(13):2375-2382.
[3]Tolkacheva T, Chan AM.Inhibition of H-Ras transformation by the PTEN/MMAC1/TEP1 tumor suppressor gene.Oncogene,2000,19(5):680-689.
[4]Tamara M, Gu J, Matsumoto K, etal.Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN.Science,1998,280(5369):1614-1617.
[5]Gu J, Tamara M, Yamada KM.Tumor suppressor PTEN inhibits integrin and growth factor mediated mitogen activated protein(MAP) kinase signaling pathways.J Cell Biol,1998, 143(5):1375-1383.
[6]Sun H, Lesche R, UDM, etal.PTEN modulates cell cycle progression and cell survival by regulating phosphatidy linositol-3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway.Proc Natl Acad Sci US A,1999,96(11):6199-6204.
[7]雷群英,王丽影,戴振宇,等。人肺癌细胞抑癌基因PTEN的表达与失巢凋亡的关系。生物化学与生物物理学报,2002,34(4)：463-468。
[8]Moorehead RA, Hojilla CV, De Belle I, etal.Insulin-like growth factor regulates PTEN expression in the mammary gland.J Biol Chem,2003,278(50):50422-50427.
[9]Farrow B, Evers BM.Activation of PPARC increases PTEN expression in pancreatic cancer cells[J].Biochem Biophys Res Commun,2003,301:50-53.
[10]Sukmi KP, YoonIL, Young IL.PTEN modulates insulin-like growth factor(IGF)-mediated signaling; the protein phosphatase activity of PTEN down-regulates IGF expression in hepatoma cells[J].FEBSLetters,2003,545:203-208.
[11]Weng LP, Brown JL, Eng C.PTEN coordinates G(1) arrest by down-regulating cyclin D1 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a breast cancer model[J].Hum Mol Genet,2001,10:599-604.
[12]Leslie NR, Bennett D, Lindsay YE, etal.Redox regulation of PI3-kinase signaling via inactivation of PTEN.EMBOJ,2003,22(20):5501-5510.
[13]Wu RC, Li X, Schonthal AH.Transcriptional activation of p21WAF1 by PTEN/MMAC1 tumor suppressor.Mol Cell Biochem,2000,203(122):59-71.
[14]Schwartzbauer G, Robbins J.The tumor suppressor gene PTEN can regulate cardiac hypertrophy and survival.J Biol Chem,2001(38),276:35786-35793.
[15]Michael A, Crackower, Gavin Y, etal.Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways[J].Cell,2002,110:737-749.
[16]Pamela J,Garl JM,Wenzlau HA, etal.Perle can induced suppression of smooth muscle cell proliferation is mediated through increased activity of the tumor suppressor PTEN[J].Circ Res,2004,94:175-183.
[17]程刚,徐耕,单江,等.辛伐他汀抑制胎牛血清及PDGF-BB诱导的血管平滑肌细胞增殖及对抑癌基因PTEN表达的影响[J].中国病理生理杂志,2002,8：830-833.
[18]单江,程刚,傅国胜.辛伐他汀抑制血管平滑肌细胞增殖及对PTEN、p27蛋白表达的影响[J].中华心血管病杂志,2002,30：622-625.
[19]吴兴利,王士雯,杨中苏,等.氧化型低密度脂蛋白对血管平滑肌细胞磷酸酶PTEN活性的影响[J].中国动脉硬化杂志,2002,10：505-508.
[20]Weiser-Evans MC, Quinn BE, Burkard MR, etal.Transient-reexpression of an embryonic autonomous growth phenotype by adult carotid artery smooth muscle cells after vascular injury.J Cell Physiol,2000,182(1):12-23.
[21]严志强,衣听,马红萍.肿瘤抑制因子PTEN蛋白在自发性高血压大鼠主动脉平滑肌中的表达.南通医学院学报,2002,22(2)：130-131.
[22]Huang J, Kontos CD.Inhibition of vascular smooth muscle cell proliferation, migration, and survival by the tumor suppressor protein PTEN.Arterioscler Thromb Vasc Biol, 2002,22(5):745-751.
[23]Huang J, Niu XLM.Pippen A, etal.Adenovirus-mediated intraarterial delivery of PTEN inhibits neointimal hyperplasia.Arterioscler Thromb Vasc Biol,2005,25(11):354-358.
[24]Garl PJ, Wenzlau JM, Walker HA, etal.Perlecan-induced suppression of smooth muscle cell proliferation is mediated through increased activity of the tumor suppressor PTEN.Circ Res,2004,94(12):175-183.
[25]Chen WJ, Lin KH, Lai YJ, etal.Protective effect of propylthiouracil independent of its hypothyroid effect on atherogenesis in cholesterol-fed rabbits:PTEN induction and inhibiton of vascular smooth muscle cell proliferation and migration.Circulation.2004,110(8):1313-1319.
[26]M Mourani P, J Carl P, M Wenzlau J, etal.Unique, highly proliferative growth phenotype expressed by embryonic and neointimal smooth muscle cells is driven by constitutive Akt, mTOR, and p70S6K signaling and is actively repressed by PTEN.Circulation,2004, 109(3):1299-1306.
[27]Koide S, Okazaki M, Tamura M, etal.PTEN reduces cuff- induced neointima formation and proinflammatory cytokines.Am J Physiol Heart Circ Physiol,2007,292(2): H2824-H2831.
[28]Lal BK.Recurrent Carotid Stenosis after CEA and CAS:Diagnosis and Management[J].Semin Vasc Surg(S0895-7967),2007,20(4):259-266.
[29]Hodgson CP, Solaiman R, Virosomes. Cationic liposomes enhance retroviral transduction. Nature Bio,1996,14:339-342.
[30]滕志涛,蔡尚郎,沃金善,等.Abciximab对动脉损伤后血清一氧化氮和内皮素水平的影响.中国介入心脏病学杂志,2004,12：51-52.
[31]胡涛,郭文怡,贾国良.血管内皮细胞及功能在经皮冠状动脉成形术后再狭窄中的作用.中国综合临床,2001,17：242-243.
[32]陆平,盛净.内皮素受体抗体与PCI术后再狭窄的防治.心血管病学进展,2004,25：387-389.
[33]李俊峡,李佃贵,李振彬.粉防己碱对血管平滑肌细胞增殖及相关基因表达的影响.心肺血管病杂志,2002,21：170-174.
[34]何冉,邱春光,韩战营,等.辛伐他汀预处理对择期PCI术后内皮素-1、NO的影响.河南医学研究,2006,15：229-231.
[35]Sato J, Mohacsi T, Noel A, et al.In vivo gene transfer of endothelial nitric oxide synthase to carotid arteries from hypercholesterolemic rabbits enhances endothelium-dependent relaxations.Stroke,2000,31:968-975.
[36]Harris MB, Ju H, Venema VJ, et al.Role of heat shock protein 90 in bradykinin-stimulated endothelial nitric oxide release.Gen Pharmacol,2000,35:165-170.
[37]Pritchard KA, Ackerman AW, Gross ER, et al.Heat shock protein 90 mediates the balance of nitric oxide and superoxide anion from endothelial nitric-oxide synthase.J Biol Chem,2001,276:17621-17624.
[381陈磊磊,龙明智.PCI术后再狭窄的预防及治疗进展.医学综述,2003,9：528-531.
[39]Mori E, Komori K, Yamaoka T, et al.Essential role of monocyte chemoattractant protein-1 in development of restenotic changes(neointimal hyperplasia and constrictive remodeling)after balloon angio- plasty in hypercholesterolemic rabbits.Circulation,2002,105: 2905-2910.
[40]Welt FG, Edelman ER, Simon DI, et al.Neutrophil, not macrophage, infiltration precedes neointimal thickening in balloon injured arteries.Arterioscler Thromb Vasc Biol, 2000,20:2553-2558.
[41]Greaves DR, Channon KM.Inflammation and immune responses in atherosclerosis.Trends Immunol,2002,23:535-541.
[42]唐镒达,陈纪林,阮英茆,等.阿司匹林抑制动脉粥样硬化炎症反应机制的初步探讨.中国循环杂志,2004,19：48-51.
[43]Libby P, Ridker PM, Maseri A.Inflammation and atherosclerosis.Circulation,2002, 105:1135-1143.
[44]Klinkhardt U, Graff J, Harder S.Clopidogrel, but not abciximab, reduces platelet leukocyte conjugates and Pselectin expression in human ex vivomodel.Clin Pharmacol Ther, 2002,71:176-185.
[45]Massberg S, Brand K, Gruner S, et al.A critical role of platelet adhesion in the ininiation of atherosclerotic lesion formation.J Exp Med,2002,196:887-897.
[46]Bienvenu JG, Tanguay JF, Chauvet P, et al.Relationship between platelets and neutrophil adhesion and neointimal growth after repeated arterial wall injury by angioplasty in pigs.J Vase Res,2001,38:153-162.
[47]Lee T, Esemuede N, Sumpio BE, et al.Thrombospondinl induces matrix metalloproteinase-2 activation in vascular smooth muscle cells.J Vasc Surg,2003,38:147-154.
[48]Hou G, Mulholland D, Gronska MA, et al.TypeⅧcollagen stimulates smooth muscle cell migrationand matrix metalloproteinase synthesis after arterial injury.Am Pathol,2000,156: 467-476.
[49]Ivian V, Fonseca A, Diez J, Decreasing restenosis following angioplasty The potential of peroxisome proliferatoractivated receptor gamma agonists.Diabetes Care,2004,27: 2764-2766.
[50]Bmemmer D, Blaschke F, Law RE.New targets for PPAR gamma in the vessel wall implications for stenosis.Int J Obes(Lond),2005(Suppl 1):S26-S30.
[51]Peterson TJ, Li H, Dillon L, et al. Evaluation of matrix metallo proteinase and tissue inhibitor expression during heart failure progression in the infarction rat.Cardiovasc Res,2000, 46:307-315.
[52]Spinale FG, Coker ML, Bond BR, et al.Myocardial matrix degradation and matelloproteinase activation in the failing eart:a potential therapeutic target.Cardiovasc Res, 2000,46:225-238.
[53]张恩光,张怀勤,林捷,等.基质金属蛋白酶在心肌缺血大鼠心室间质重构中的作用.中国病理生理杂志,2003,19：653-656.
[54]张子新,曾定尹,王绽菲.基质金属蛋白酶及其抑制剂在家兔血管成形术后血管重构中的作用.中国病理生理杂志,2005,21：1503-1507.
[55]Yang ZY, Siari RD, Perkins ND, et al.Role of P21 Cyclin-dependent kinase inhibitor in limiting intimal cell proliferation in response to arterial injury[J].Proc Natl Acad Sci USA, 1996,93:7905-7910-
[56]Mastsushita H, Morishita R, Kida I, et al.Inhibition of growth of human Vascular smooth muscle cells by over expression of P21 gene through induction of apoptosis[J].Hypertension,1998,31(1 pt 2):493-498-
[57]苏津自,吴可贵,李庚山等。原癌基因c-myc核酶表达载体抑制血管平滑肌细胞的表达。中华高血压杂志(Chin J Hypertension), Nov 2006, Vol.14, No 11:903-908。
[58]王启贤,肖丽梅,郝萍,等。反义凝血酶受体ODNs对大鼠血管平滑肌细胞增殖的影响。昆明医学院学报2004,(4)：21-26。
[59]Chang MW, Barr E, Seltzer J, eta.l Cytostatic gene therapy forvascularproliferative disorderswith a constrictive active form of the retinoblastoma gene product[J]. Science,1995, 267(5197):518-522.
[60]Dollery CM, Humphries SE, Mcclelland A, et a.l Expression of tissue inhibitor ofmatrixmetalloproteinases 1 by use of an denoviral vector inhibits smoothcellmigration and reduce sneointimal hyperplasia in the ratmodel of vascular balloon injury[J].Circulation,1999, 99(24):3199-3205.
[61]Rutanen J, Turunen AM, Teittinen M, eta.l Gene transferusing themature form of VEGF-D reduces neointimal thickening through nitricoxide-dependentmechanism[J].GeneTher, 2005,12(12):980-987.
[62]Varenne O, Sinnaeve P, Gillijns H, et a.l Percutaneous gene therapy using recombinant adenoviruses encodinghuman herps simplex virus thymidine kinase, human PAI-1, and human NOS3 in balloon-injured porcine coronary arteries[J].Hum GeneTher,2000, 11(9):1329-1339.
[63]周玉杰,汪丽慧,周爱儒,等.反义N-ras基因对血管损伤后平滑肌细胞增殖的影响[J].中华医学杂志,1997,77：66-69.
[64]Fukuda N, Kubo A, WatanabeY, eta.l Antisense oligodeoxynucleotide complementary to platelet-derived growth factorA-chain messenger rRNA inhibits the arterial proliferation in spontaneously hypertensive rats without altering their blood pressures[J]. JHypertens,1997,15(10):1123-1136.
[65]Morishita R, Gibbons GH, Horiuchi M, et a.l A novelmolecular strategy using cis element"decoy"ofE2F binding sit inhibits smooth muscle proliferation in vivo[J].ProcNatlAcad SciUSA,1995,92:5855-5859.
[66]Yoshimura S, Morishita R, Hayashi K, eta.l Inhibition of intimalhyperplasia after balloon injury in rat carotid arterymodel using cis-element"decoy"of nuclear factor-kappa B binding site as a novelmolecular strategy[J].GeneTher,2001,8(21):1635-1642.
[67]Morishita R. Recent progress in gene therapy for cardiovascular disease[J].Circ J, 2002,66:1077-1086.
[68]SoRelle R.Late-breaking clinical trails at theAmericanHeartAssociations' scientific sessions 2001 [J].Circulation,2001,104:E9046-E9048.
[69]吕一峰,郑家豪.“诱骗”策略预防冠脉再狭窄的研究进展[J].中国心血管病研究杂志,2005,3(5)：384-387.
[70]Sipe KJ, Dantzer R, Kelley KW, et al. Expression of the 75kDA TNF receptor and its role in contact-mediated neuronal cell death. Brain Res Mol Brain Res,1998,62(2): 111-121.
[71]Smith MR, Duhe RJ, Liu Y, et al. Microinjected cDNA encoding JAK2 protein-tyro sine kinase induces DNA synthesis in NIH3T3 cells. Febs Lett,1997,408(5): 327-330.
[72]Toby G, Law SF, Golemis EA. Vectors to target protein domains to different cellular compartments. Biotechniques,1998,24(11):637-640.
[73]Flaxel CJ. Use of radiation in the reatment of age-related macular degeneration. Ophthalmol Clin North Am,2002,15:437-444.
[74]Donati C. Current treatment of choroidal neovascularization in age-related macular degeneration. J Fr Ophtalmol,2002,25:740-746.
[75]Dobi ET,Puliafito CA, Destro M. A new model of experimental choroidal neovascularization in the rat. Arch Ophthalmol,1989,107(2):264-269.
[76]Nilsson J.Cytokines and smooth muscle cells in atherosclerosis.Cardio-vas Res,1993, 27:1184-1190.
[77]Kahari VM, Chen YQ, Su MW, et al.Tumor necrosis factor-αand interferon-ysuppress the activation of human type Ⅰ collagen gene expression by trasforming growth factor-β1. Evidence for two distinct mechanisms of inhibition at the transcriptional and post-transcriptional levels.J Clin Inves,1990,86:1489-1495.
[78]Faries PL, Rohan DI, Wyers MC, et al.Vascular smooth muscle cells derived from atherosclerotic human arteries exhibit greater adhesion, migration, and proliferation than venous cells.J Surg Res.2002; 104(1):22-8.
[79]ZhiLiu, PengHou, Meiju Ji etal.Highly Prevalent Genetic Alterations in Receptor Tyrosine kinases and PI3K/Akt and MAP kinase Pathways in AnaPlastic and Follicular Thyroid Cancer [J].J Clin Endocrin Metab.2008,5(20):2008-2073.
[80]胡蕾、姜汉国,PI3K/Akt信号转导通路与肿瘤转移及其机制的研究进展[J].医学综述.2006,12(22)：p.1375-1377.
[81]Braun-Dullaeus RC, Mann MJ, Seay U, Zhang L, von Der Leyen HE, Morris RE, Dzau VJ. Cell cycle protein expression in vascular smooth muscle cells in vitro and in vivo is regulated through phosphatidylinositol 3-kinase and mammalian target of rapamycin. Arterioscler Thromb Vasc Biol.2001; 21:1152-1158.
[82]Shigematsu K, Koyama H, Olson NE, Cho A, Reidy MA. Phosphatidylinositol 3-kinase signaling is important for smooth muscle cell replication after arterial injury. Arterioscler Thromb Vase Biol.2000; 20:2373-2378.
[83]Vanhaesebroeck B, Alessi DR. The PI 3K-PDK1 connection:more than just a road to PKB. Biochem J.2000; 346(pt 3):561-576.
[84]Stephens L, Anderson K, Stokoe D, Erdjument-Bromage H, Painter GF, Holmes AB, Gaffney PR, Reese CB, McCormick F, Tempst P, Coadwell J, Hawkins PT. Protein kinase B kinases that mediate phosphatidylinositol 3,4,5- trisphosphate-dependent activation of protein kinase B. Science.1998; 279:710-714.
[85]Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA, Thomas G. Phosphorylation and activation of p70s6k by PDK1. Science.1998; 279:707-710.
[86]Downward J. Mechanisms and consequences of activation of protein kinase B/Akt. Curr Opin Cell Biol.1998; 10:262-267.
[87]于宝华,周晓燕PI3K/Akt/mTQR的信号传到通路在恶性肿瘤中的研究进展[J].中华病理学杂志,2005,34(10)：674—676.
[88]Cannen BA, Oliver Renner, Juan F M L, etal.PTEN, more than the Akt Pathway[J].Careinogenesis.2007,28(7):1379-1386.
[89]Sarbassov D D, Guertin D A, Ali S M, etal.Phos Phorylation and regulation of AKt/PKB by the rictor-mTOR complex[J].Science.2005,307(5712):1098-1101.
[90]Myers MP, Pass I, Batty IH, Van Wigler MH, Downes CP, Tonks NK.der Kaay J, Stolarov JP, Hemmings BA, The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci,1998,95(23):13513-13518.
[91]KemPe S, Kestler H, Lasar A, etal.NF-kaPPa B controls the global Pro-inflamatory response in endothelial cells:evidence for the regulation of a Proatherogenic Program[J].Nucleic Acids Res.2005,33(16):5308-5319.
[92]Sayako H, Tasuku H, Masahiro M, etal.Progesterone and Progestational Compounds attenuate tumor necrosis factor alPha-induced interleukin-8 Produetion Via nuclear factor kappaB inactivation in endometriotic stromal cells[J].Fertility And Sterility.2005,88(5): 1530-1535.
[93]Li DM, H Sun, TEPI, encoded by a candidate tumor suppressor locus, is a novel Protein tyrosine PhosPhatase regulated by transforming growth factor beta[J].Cancer research.1997,57(12); 2124-9.
[94]Gustin JA, Ozes ON, Akea H, etal.Cell type-specific expression of the IkappaB Kinases determines the significance of Phosphatidylinositol 3-kinase/Akt signaling to NF-kappaB activation[J].J Biol Chem.2004,279(3):1615-1620.
[95]Meng F and D'Mello SR.NF-kaPPaB stimulate Akt PhosPhorylation and gene expression by distinct signaling mechanisms[J].Biochim Biophys Acta.2003,1630(1):352401.
[96]Chen SW, Li XH, Ye KH, et al.Total saponins of Panax notoginseng
protected rabbit iliac artery against balloon endothelial denudation injury[J].Acta Pharmacol Sin,2004,25(9):1151-1156.
[97]Seppo YHet al. Lancet,2000,355:213-219
[98]李拥军等.中国动脉硬化杂志,2001,9(1)：77-80
[99]梁宏立.国外医学：心血管疾病分册,2000,27(1)：7
[100]Tahlil Oet al. Cardiovasc Res,1997,33:181-187
[101]Veit K, Boissel JP, Buerke M, et al.Highly efficient liposome-mediated gene transfer of inducible nitric oxide synthase in vivo and in vitro in vascularsmooth muscle cells.Cardiovasc Res.1999; 43(3):808-22.
[102]Geary RL, Williams JK, Golden D, et al.Time course of celluar of proliferation, intimal hyperplasia, and remodeling following angioplasty in monkeys with established atheroselerosis. Arterioselerosis, Thlombosis, and Vascular Biology.1996; 16:34-43.
[103]Gearyr L, Williams JK, Golden D, et al. Time course of cellular
proliferation, intimal hyperplasia, and remodeling following angioplasty in monkeys with established atherosclerosis (a nonhuman primate model of restenosis) [J]. Arterioscler Thromb Vasc Biol 1996,16(1):34-43
[104]Zempo N, Kenagy RD, Au YP, et al.Matrix metalloproteinases of vascular wall cells are increased in balloon-injured rat carotid artery.J Vasc Surg.1994 Aug; 20(2):209-17.
[105]Fingerle J, Au YP, Clowes AW, et al.Intimal lesion formation in rat carotid arteries after endothelial denudation in absence of medial injury. Arteriosclerosis.1990; 10(6):1082-7.
[106]Signore PE, Machan LS, Jackson JK, et al.Complete inhibition of intimal hyperplasia by perivascular delivery of paclitaxel in balloon-injured rat carotidarteries.J Vasc Interv Radiol.2001 Jan; 12(1):79-88.
[107]Lamfers ML, Lardenoye JH, de Vries MR, et al.In vivo suppression of restenosis in balloon-injured rat carotid artery by adenovirus-mediated gene transfer of the cell surface-directed plasmin inhibitor ATF.BPTI.Gene Ther.2001 Apr; 8(7):534-41.
[108]Ascher E, Scheinman M, Hingorani A, et al.Effect of p53 gene therapy combined with CTLA4lg selective immunosuppression on prolonged neointima formation reduction in a rat model.Ann Vasc Surg.2000 Jul; 14(4):385-92.
[109]Kitazume H, Kubo I, Iwama T,et al. Long-term angiographic follow-up of lesions patent 6 months aftecpercutaneous coronary angioplasty [J]. Am Heart J,1995,129(3): 441-444.
[110]Gibbons GH, Dzau VJ. The emerging concept of vascular remodeling. N Engl J Med.1994; 330:1431-1438.
[111]Braun-Dullaeus RC, Mann MJ, Dzau VJ. Cell cycle progression:new therapeutic target for vascular proliferative disease. Circulation.1998; 98:82-89.
[112]Sousa JE, Costa MA, Abizaid AC, RensingBJ, Abizaid AS, Tanajura LF, Kozuma K, Van Langenhove G, Sousa AG, Falotico R, Jaeger J, Popma JJ, Serruys PW. Sustained suppression of neointimal proliferation by sirolimus-eluting stents:one-year angiographic and intravascular ultrasound follow-up. Circulation.2001; 104:2007-2011
[113]Tanabe K, Degertekin M, Regar E, Ligthart JM, van der Giessen WJ, Serruys PW. No delayed restenosis at 18 months after implantation of sirolimus-eluting stent. Catheter Cardiovasc Int.2002; 57:65-68
[114]Saia F, Lemos PA, Sianos G, Degertekin M, Lee CH, Arampatzis CA, Hoye A, Tanabe K, Regar E, van der Giessen WJ, Smits PC, de Feyter P, Ligthart J, van Domburg RT, Serruys PW. Effectiveness of sirolimus-eluting stent implantation for recurrent in-stent restenosis after brachytherapy. Am J Cardiol.2003:92:200-203.
[115]Gingras AC, Raught B, Sonenberg N. Regulation of translation initiation by FRAP/mTOR. Genes Dev.2001; 15:807-826.
[116]Rameh LE, Cantley LC. The role of phosphoinositide 3-kinase lipid products in cell function. J Biol Chem.1999; 274:8347-8350.
[117]Shigematsu K, Koyama H, Olson NE, Cho A, Reidy MA. Phosphatidylinositol 3-kinase signaling is important for smooth muscle cell replication after arterial injury. Arterioscler Thromb Vasc Biol.2000; 20:2373-2378.
[118]Zhou RH, Lee TS, Tsou TC, Rannou F, Li YS, Chien S, Shyy JY. Stent implantation activates Akt in the vessel wall:role of mechanical stretch in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol.2003; 23:2015-2020.
[119]Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem.1998; 273:13375-13378.
[120]Malemud CJ.Matrix metalloproteinases(MMPs)in health and disease:an overview[J].Front Biosci,2006,11:1696-1701
[121]Aoyagi M, Yamamoto M, Azuma H, et al.Immunolocalization of matrix metalloproteinases in rabbit carotid arteries after balloon denudation[J].Histochem Cell Biol, 1998,109(2):97-102.
[122]Moon SK, Kim HM, Kim CH. PTEN induces G1 cell cycle arrest and inhibits MMP-9 expression via the regulation of NF-kappaB and AP-1 in vascular smooth muscle cells. Arch Biochem Biophys.2004; 421:267-276.
[123]Weng LP, Brown JL, Eng C. PTEN coordinates G(1) arrest by down-regulating cyclin D1 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a breast cancer model. Hum Mol Genet.2001; 10:599-604.
[124]Sun H, Lesche R, Li DM, Liliental J, Zhang H, Gao J, Gavrilova N, Mueller B, Liu X, Wu H. PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway. Proc Natl Acad Sci U S A.1999; 96:6199-6204.
[125]Cantley LC, Neel BG. New insights into tumor suppression:PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A,1999; 96:4240-4245.
[126]Sata M, Tanaka K, Ishizaka N, Hirata Y, Nagai R. Absence of p53 Leads to Accelerated Neointimal Hyperplasia After Vascular Injury. Arterioscler Thromb Vasc Biol. 2003; 23:1548-1552
[127]Vazquez F, Ramaswamy S, Nakamura N, Sellers WR. Phosphorylation of the PTEN tail regulates protein stability and function. Mol Cell Biol.2000; 20:5010-5018
[128]Vazquez F, Grossman SR, Takahashi Y, Rokas MV, Nakamura N, Sellers WR. Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex. J Biol Chem.2001; 276:48627-48630.
[129]Torres J, Pulido R. The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome- mediated degradation. J Biol Chem.2001; 276:993-998.
[130]Torres J, Rodriguez J, Myers MP, Valiente M, Graves JD, Tonks NK, Pulido R. Phosphorylation-regulated cleavage of the tumor suppressor PTEN by caspase-3: implications for the control of protein stability and PTEN-protein interactions. J Biol Chem. 2003; 278:30652-30660.
[131]Lee SR, Yang KS, Kwon J, Lee C, Jeong W, Rhee SG. Reversible inactivation of the tumor suppressor PTEN by H2O2. J Biol Chem.2002; 277:.20336-20342.
[132]Wu W, Wang X, Zhang W, Reed W, Samet JM, Whang YE, Ghio AJ. Zinc-induced PTEN protein degradation through the proteasome pathway in human airway epithelial cells. J Biol Chem.2003; 278:28258-28263.
[2]Yamada KM, Araki M.Tumor suppressor PTEN:modulator of cell singaling, growth, migration and apoptosis.J Cell Sci,2001,114(13):2375-2382.
[3]Tolkacheva T, Chan AM.Inhibition of H-Ras transformation by the PTEN/MMAC1/TEP1 tumor suppressor gene.Oncogene,2000,19(5):680-689.
[4]Tamara M, Gu J, Matsumoto K, etal.Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN.Science,1998,280(5369):1614-1617.
[5]Gu J, Tamara M, Yamada KM.Tumor suppressor PTEN inhibits integrin and growth factor mediated mitogen activated protein(MAP) kinase signaling pathways.J Cell Biol,1998, 143(5):1375-1383.
[6]Sun H, Lesche R, UDM, etal.PTEN modulates cell cycle progression and cell survival by regulating phosphatidy linositol-3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway.Proc Natl Acad Sci US A,1999,96(11):6199-6204.
[7]雷群英,王丽影,戴振宇,等。人肺癌细胞抑癌基因PTEN的表达与失巢凋亡的关系。生物化学与生物物理学报,2002,34(4)：463-468。
[8]Moorehead RA, Hojilla CV, De Belle I, etal.Insulin-like growth factor regulates PTEN expression in the mammary gland.J Biol Chem,2003,278(50):50422-50427.
[9]Farrow B, Evers BM.Activation of PPARC increases PTEN expression in pancreatic cancer cells[J].Biochem Biophys Res Commun,2003,301:50-53.
[10]Sukmi KP, YoonIL, Young IL.PTEN modulates insulin-like growth factor(IGF)-mediated signaling; the protein phosphatase activity of PTEN down-regulates IGF expression in hepatoma cells[J].FEBSLetters,2003,545:203-208.
[11]Weng LP, Brown JL, Eng C.PTEN coordinates G(1) arrest by down-regulating cyclin D1 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a breast cancer model[J].Hum Mol Genet,2001,10:599-604.
[12]Leslie NR, Bennett D, Lindsay YE, etal.Redox regulation of PI3-kinase signaling via inactivation of PTEN.EMBOJ,2003,22(20):5501-5510.
[13]Wu RC, Li X, Schonthal AH.Transcriptional activation of p21WAF1 by PTEN/MMAC1 tumor suppressor.Mol Cell Biochem,2000,203(122):59-71.
[14]Schwartzbauer G, Robbins J.The tumor suppressor gene PTEN can regulate cardiac hypertrophy and survival.J Biol Chem,2001(38),276:35786-35793.
[15]Michael A, Crackower, Gavin Y, etal.Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways[J].Cell,2002,110:737-749.
[16]Pamela J,Garl JM,Wenzlau HA, etal.Perle can induced suppression of smooth muscle cell proliferation is mediated through increased activity of the tumor suppressor PTEN[J].Circ Res,2004,94:175-183.
[17]程刚,徐耕,单江,等.辛伐他汀抑制胎牛血清及PDGF-BB诱导的血管平滑肌细胞增殖及对抑癌基因PTEN表达的影响[J].中国病理生理杂志,2002,8：830-833.
[18]单江,程刚,傅国胜.辛伐他汀抑制血管平滑肌细胞增殖及对PTEN、p27蛋白表达的影响[J].中华心血管病杂志,2002,30：622-625.
[19]吴兴利,王士雯,杨中苏,等.氧化型低密度脂蛋白对血管平滑肌细胞磷酸酶PTEN活性的影响[J].中国动脉硬化杂志,2002,10：505-508.
[20]Weiser-Evans MC, Quinn BE, Burkard MR, etal.Transient-reexpression of an embryonic autonomous growth phenotype by adult carotid artery smooth muscle cells after vascular injury.J Cell Physiol,2000,182(1):12-23.
[21]严志强,衣听,马红萍.肿瘤抑制因子PTEN蛋白在自发性高血压大鼠主动脉平滑肌中的表达.南通医学院学报,2002,22(2)：130-131.
[22]Huang J, Kontos CD.Inhibition of vascular smooth muscle cell proliferation, migration, and survival by the tumor suppressor protein PTEN.Arterioscler Thromb Vasc Biol, 2002,22(5):745-751.
[23]Huang J, Niu XLM.Pippen A, etal.Adenovirus-mediated intraarterial delivery of PTEN inhibits neointimal hyperplasia.Arterioscler Thromb Vasc Biol,2005,25(11):354-358.
[24]Garl PJ, Wenzlau JM, Walker HA, etal.Perlecan-induced suppression of smooth muscle cell proliferation is mediated through increased activity of the tumor suppressor PTEN.Circ Res,2004,94(12):175-183.
[25]Chen WJ, Lin KH, Lai YJ, etal.Protective effect of propylthiouracil independent of its hypothyroid effect on atherogenesis in cholesterol-fed rabbits:PTEN induction and inhibiton of vascular smooth muscle cell proliferation and migration.Circulation.2004,110(8):1313-1319.
[26]M Mourani P, J Carl P, M Wenzlau J, etal.Unique, highly proliferative growth phenotype expressed by embryonic and neointimal smooth muscle cells is driven by constitutive Akt, mTOR, and p70S6K signaling and is actively repressed by PTEN.Circulation,2004, 109(3):1299-1306.
[27]Koide S, Okazaki M, Tamura M, etal.PTEN reduces cuff- induced neointima formation and proinflammatory cytokines.Am J Physiol Heart Circ Physiol,2007,292(2): H2824-H2831.
[28]Lal BK.Recurrent Carotid Stenosis after CEA and CAS:Diagnosis and Management[J].Semin Vasc Surg(S0895-7967),2007,20(4):259-266.
[29]Hodgson CP, Solaiman R, Virosomes. Cationic liposomes enhance retroviral transduction. Nature Bio,1996,14:339-342.
[30]滕志涛,蔡尚郎,沃金善,等.Abciximab对动脉损伤后血清一氧化氮和内皮素水平的影响.中国介入心脏病学杂志,2004,12：51-52.
[31]胡涛,郭文怡,贾国良.血管内皮细胞及功能在经皮冠状动脉成形术后再狭窄中的作用.中国综合临床,2001,17：242-243.
[32]陆平,盛净.内皮素受体抗体与PCI术后再狭窄的防治.心血管病学进展,2004,25：387-389.
[33]李俊峡,李佃贵,李振彬.粉防己碱对血管平滑肌细胞增殖及相关基因表达的影响.心肺血管病杂志,2002,21：170-174.
[34]何冉,邱春光,韩战营,等.辛伐他汀预处理对择期PCI术后内皮素-1、NO的影响.河南医学研究,2006,15：229-231.
[35]Sato J, Mohacsi T, Noel A, et al.In vivo gene transfer of endothelial nitric oxide synthase to carotid arteries from hypercholesterolemic rabbits enhances endothelium-dependent relaxations.Stroke,2000,31:968-975.
[36]Harris MB, Ju H, Venema VJ, et al.Role of heat shock protein 90 in bradykinin-stimulated endothelial nitric oxide release.Gen Pharmacol,2000,35:165-170.
[37]Pritchard KA, Ackerman AW, Gross ER, et al.Heat shock protein 90 mediates the balance of nitric oxide and superoxide anion from endothelial nitric-oxide synthase.J Biol Chem,2001,276:17621-17624.
[381陈磊磊,龙明智.PCI术后再狭窄的预防及治疗进展.医学综述,2003,9：528-531.
[39]Mori E, Komori K, Yamaoka T, et al.Essential role of monocyte chemoattractant protein-1 in development of restenotic changes(neointimal hyperplasia and constrictive remodeling)after balloon angio- plasty in hypercholesterolemic rabbits.Circulation,2002,105: 2905-2910.
[40]Welt FG, Edelman ER, Simon DI, et al.Neutrophil, not macrophage, infiltration precedes neointimal thickening in balloon injured arteries.Arterioscler Thromb Vasc Biol, 2000,20:2553-2558.
[41]Greaves DR, Channon KM.Inflammation and immune responses in atherosclerosis.Trends Immunol,2002,23:535-541.
[42]唐镒达,陈纪林,阮英茆,等.阿司匹林抑制动脉粥样硬化炎症反应机制的初步探讨.中国循环杂志,2004,19：48-51.
[43]Libby P, Ridker PM, Maseri A.Inflammation and atherosclerosis.Circulation,2002, 105:1135-1143.
[44]Klinkhardt U, Graff J, Harder S.Clopidogrel, but not abciximab, reduces platelet leukocyte conjugates and Pselectin expression in human ex vivomodel.Clin Pharmacol Ther, 2002,71:176-185.
[45]Massberg S, Brand K, Gruner S, et al.A critical role of platelet adhesion in the ininiation of atherosclerotic lesion formation.J Exp Med,2002,196:887-897.
[46]Bienvenu JG, Tanguay JF, Chauvet P, et al.Relationship between platelets and neutrophil adhesion and neointimal growth after repeated arterial wall injury by angioplasty in pigs.J Vase Res,2001,38:153-162.
[47]Lee T, Esemuede N, Sumpio BE, et al.Thrombospondinl induces matrix metalloproteinase-2 activation in vascular smooth muscle cells.J Vasc Surg,2003,38:147-154.
[48]Hou G, Mulholland D, Gronska MA, et al.TypeⅧcollagen stimulates smooth muscle cell migrationand matrix metalloproteinase synthesis after arterial injury.Am Pathol,2000,156: 467-476.
[49]Ivian V, Fonseca A, Diez J, Decreasing restenosis following angioplasty The potential of peroxisome proliferatoractivated receptor gamma agonists.Diabetes Care,2004,27: 2764-2766.
[50]Bmemmer D, Blaschke F, Law RE.New targets for PPAR gamma in the vessel wall implications for stenosis.Int J Obes(Lond),2005(Suppl 1):S26-S30.
[51]Peterson TJ, Li H, Dillon L, et al. Evaluation of matrix metallo proteinase and tissue inhibitor expression during heart failure progression in the infarction rat.Cardiovasc Res,2000, 46:307-315.
[52]Spinale FG, Coker ML, Bond BR, et al.Myocardial matrix degradation and matelloproteinase activation in the failing eart:a potential therapeutic target.Cardiovasc Res, 2000,46:225-238.
[53]张恩光,张怀勤,林捷,等.基质金属蛋白酶在心肌缺血大鼠心室间质重构中的作用.中国病理生理杂志,2003,19：653-656.
[54]张子新,曾定尹,王绽菲.基质金属蛋白酶及其抑制剂在家兔血管成形术后血管重构中的作用.中国病理生理杂志,2005,21：1503-1507.
[55]Yang ZY, Siari RD, Perkins ND, et al.Role of P21 Cyclin-dependent kinase inhibitor in limiting intimal cell proliferation in response to arterial injury[J].Proc Natl Acad Sci USA, 1996,93:7905-7910-
[56]Mastsushita H, Morishita R, Kida I, et al.Inhibition of growth of human Vascular smooth muscle cells by over expression of P21 gene through induction of apoptosis[J].Hypertension,1998,31(1 pt 2):493-498-
[57]苏津自,吴可贵,李庚山等。原癌基因c-myc核酶表达载体抑制血管平滑肌细胞的表达。中华高血压杂志(Chin J Hypertension), Nov 2006, Vol.14, No 11:903-908。
[58]王启贤,肖丽梅,郝萍,等。反义凝血酶受体ODNs对大鼠血管平滑肌细胞增殖的影响。昆明医学院学报2004,(4)：21-26。
[59]Chang MW, Barr E, Seltzer J, eta.l Cytostatic gene therapy forvascularproliferative disorderswith a constrictive active form of the retinoblastoma gene product[J]. Science,1995, 267(5197):518-522.
[60]Dollery CM, Humphries SE, Mcclelland A, et a.l Expression of tissue inhibitor ofmatrixmetalloproteinases 1 by use of an denoviral vector inhibits smoothcellmigration and reduce sneointimal hyperplasia in the ratmodel of vascular balloon injury[J].Circulation,1999, 99(24):3199-3205.
[61]Rutanen J, Turunen AM, Teittinen M, eta.l Gene transferusing themature form of VEGF-D reduces neointimal thickening through nitricoxide-dependentmechanism[J].GeneTher, 2005,12(12):980-987.
[62]Varenne O, Sinnaeve P, Gillijns H, et a.l Percutaneous gene therapy using recombinant adenoviruses encodinghuman herps simplex virus thymidine kinase, human PAI-1, and human NOS3 in balloon-injured porcine coronary arteries[J].Hum GeneTher,2000, 11(9):1329-1339.
[63]周玉杰,汪丽慧,周爱儒,等.反义N-ras基因对血管损伤后平滑肌细胞增殖的影响[J].中华医学杂志,1997,77：66-69.
[64]Fukuda N, Kubo A, WatanabeY, eta.l Antisense oligodeoxynucleotide complementary to platelet-derived growth factorA-chain messenger rRNA inhibits the arterial proliferation in spontaneously hypertensive rats without altering their blood pressures[J]. JHypertens,1997,15(10):1123-1136.
[65]Morishita R, Gibbons GH, Horiuchi M, et a.l A novelmolecular strategy using cis element"decoy"ofE2F binding sit inhibits smooth muscle proliferation in vivo[J].ProcNatlAcad SciUSA,1995,92:5855-5859.
[66]Yoshimura S, Morishita R, Hayashi K, eta.l Inhibition of intimalhyperplasia after balloon injury in rat carotid arterymodel using cis-element"decoy"of nuclear factor-kappa B binding site as a novelmolecular strategy[J].GeneTher,2001,8(21):1635-1642.
[67]Morishita R. Recent progress in gene therapy for cardiovascular disease[J].Circ J, 2002,66:1077-1086.
[68]SoRelle R.Late-breaking clinical trails at theAmericanHeartAssociations' scientific sessions 2001 [J].Circulation,2001,104:E9046-E9048.
[69]吕一峰,郑家豪.“诱骗”策略预防冠脉再狭窄的研究进展[J].中国心血管病研究杂志,2005,3(5)：384-387.
[70]Sipe KJ, Dantzer R, Kelley KW, et al. Expression of the 75kDA TNF receptor and its role in contact-mediated neuronal cell death. Brain Res Mol Brain Res,1998,62(2): 111-121.
[71]Smith MR, Duhe RJ, Liu Y, et al. Microinjected cDNA encoding JAK2 protein-tyro sine kinase induces DNA synthesis in NIH3T3 cells. Febs Lett,1997,408(5): 327-330.
[72]Toby G, Law SF, Golemis EA. Vectors to target protein domains to different cellular compartments. Biotechniques,1998,24(11):637-640.
[73]Flaxel CJ. Use of radiation in the reatment of age-related macular degeneration. Ophthalmol Clin North Am,2002,15:437-444.
[74]Donati C. Current treatment of choroidal neovascularization in age-related macular degeneration. J Fr Ophtalmol,2002,25:740-746.
[75]Dobi ET,Puliafito CA, Destro M. A new model of experimental choroidal neovascularization in the rat. Arch Ophthalmol,1989,107(2):264-269.
[76]Nilsson J.Cytokines and smooth muscle cells in atherosclerosis.Cardio-vas Res,1993, 27:1184-1190.
[77]Kahari VM, Chen YQ, Su MW, et al.Tumor necrosis factor-αand interferon-ysuppress the activation of human type Ⅰ collagen gene expression by trasforming growth factor-β1. Evidence for two distinct mechanisms of inhibition at the transcriptional and post-transcriptional levels.J Clin Inves,1990,86:1489-1495.
[78]Faries PL, Rohan DI, Wyers MC, et al.Vascular smooth muscle cells derived from atherosclerotic human arteries exhibit greater adhesion, migration, and proliferation than venous cells.J Surg Res.2002; 104(1):22-8.
[79]ZhiLiu, PengHou, Meiju Ji etal.Highly Prevalent Genetic Alterations in Receptor Tyrosine kinases and PI3K/Akt and MAP kinase Pathways in AnaPlastic and Follicular Thyroid Cancer [J].J Clin Endocrin Metab.2008,5(20):2008-2073.
[80]胡蕾、姜汉国,PI3K/Akt信号转导通路与肿瘤转移及其机制的研究进展[J].医学综述.2006,12(22)：p.1375-1377.
[81]Braun-Dullaeus RC, Mann MJ, Seay U, Zhang L, von Der Leyen HE, Morris RE, Dzau VJ. Cell cycle protein expression in vascular smooth muscle cells in vitro and in vivo is regulated through phosphatidylinositol 3-kinase and mammalian target of rapamycin. Arterioscler Thromb Vasc Biol.2001; 21:1152-1158.
[82]Shigematsu K, Koyama H, Olson NE, Cho A, Reidy MA. Phosphatidylinositol 3-kinase signaling is important for smooth muscle cell replication after arterial injury. Arterioscler Thromb Vase Biol.2000; 20:2373-2378.
[83]Vanhaesebroeck B, Alessi DR. The PI 3K-PDK1 connection:more than just a road to PKB. Biochem J.2000; 346(pt 3):561-576.
[84]Stephens L, Anderson K, Stokoe D, Erdjument-Bromage H, Painter GF, Holmes AB, Gaffney PR, Reese CB, McCormick F, Tempst P, Coadwell J, Hawkins PT. Protein kinase B kinases that mediate phosphatidylinositol 3,4,5- trisphosphate-dependent activation of protein kinase B. Science.1998; 279:710-714.
[85]Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA, Thomas G. Phosphorylation and activation of p70s6k by PDK1. Science.1998; 279:707-710.
[86]Downward J. Mechanisms and consequences of activation of protein kinase B/Akt. Curr Opin Cell Biol.1998; 10:262-267.
[87]于宝华,周晓燕PI3K/Akt/mTQR的信号传到通路在恶性肿瘤中的研究进展[J].中华病理学杂志,2005,34(10)：674—676.
[88]Cannen BA, Oliver Renner, Juan F M L, etal.PTEN, more than the Akt Pathway[J].Careinogenesis.2007,28(7):1379-1386.
[89]Sarbassov D D, Guertin D A, Ali S M, etal.Phos Phorylation and regulation of AKt/PKB by the rictor-mTOR complex[J].Science.2005,307(5712):1098-1101.
[90]Myers MP, Pass I, Batty IH, Van Wigler MH, Downes CP, Tonks NK.der Kaay J, Stolarov JP, Hemmings BA, The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci,1998,95(23):13513-13518.
[91]KemPe S, Kestler H, Lasar A, etal.NF-kaPPa B controls the global Pro-inflamatory response in endothelial cells:evidence for the regulation of a Proatherogenic Program[J].Nucleic Acids Res.2005,33(16):5308-5319.
[92]Sayako H, Tasuku H, Masahiro M, etal.Progesterone and Progestational Compounds attenuate tumor necrosis factor alPha-induced interleukin-8 Produetion Via nuclear factor kappaB inactivation in endometriotic stromal cells[J].Fertility And Sterility.2005,88(5): 1530-1535.
[93]Li DM, H Sun, TEPI, encoded by a candidate tumor suppressor locus, is a novel Protein tyrosine PhosPhatase regulated by transforming growth factor beta[J].Cancer research.1997,57(12); 2124-9.
[94]Gustin JA, Ozes ON, Akea H, etal.Cell type-specific expression of the IkappaB Kinases determines the significance of Phosphatidylinositol 3-kinase/Akt signaling to NF-kappaB activation[J].J Biol Chem.2004,279(3):1615-1620.
[95]Meng F and D'Mello SR.NF-kaPPaB stimulate Akt PhosPhorylation and gene expression by distinct signaling mechanisms[J].Biochim Biophys Acta.2003,1630(1):352401.
[96]Chen SW, Li XH, Ye KH, et al.Total saponins of Panax notoginseng
protected rabbit iliac artery against balloon endothelial denudation injury[J].Acta Pharmacol Sin,2004,25(9):1151-1156.
[97]Seppo YHet al. Lancet,2000,355:213-219
[98]李拥军等.中国动脉硬化杂志,2001,9(1)：77-80
[99]梁宏立.国外医学：心血管疾病分册,2000,27(1)：7
[100]Tahlil Oet al. Cardiovasc Res,1997,33:181-187
[101]Veit K, Boissel JP, Buerke M, et al.Highly efficient liposome-mediated gene transfer of inducible nitric oxide synthase in vivo and in vitro in vascularsmooth muscle cells.Cardiovasc Res.1999; 43(3):808-22.
[102]Geary RL, Williams JK, Golden D, et al.Time course of celluar of proliferation, intimal hyperplasia, and remodeling following angioplasty in monkeys with established atheroselerosis. Arterioselerosis, Thlombosis, and Vascular Biology.1996; 16:34-43.
[103]Gearyr L, Williams JK, Golden D, et al. Time course of cellular
proliferation, intimal hyperplasia, and remodeling following angioplasty in monkeys with established atherosclerosis (a nonhuman primate model of restenosis) [J]. Arterioscler Thromb Vasc Biol 1996,16(1):34-43
[104]Zempo N, Kenagy RD, Au YP, et al.Matrix metalloproteinases of vascular wall cells are increased in balloon-injured rat carotid artery.J Vasc Surg.1994 Aug; 20(2):209-17.
[105]Fingerle J, Au YP, Clowes AW, et al.Intimal lesion formation in rat carotid arteries after endothelial denudation in absence of medial injury. Arteriosclerosis.1990; 10(6):1082-7.
[106]Signore PE, Machan LS, Jackson JK, et al.Complete inhibition of intimal hyperplasia by perivascular delivery of paclitaxel in balloon-injured rat carotidarteries.J Vasc Interv Radiol.2001 Jan; 12(1):79-88.
[107]Lamfers ML, Lardenoye JH, de Vries MR, et al.In vivo suppression of restenosis in balloon-injured rat carotid artery by adenovirus-mediated gene transfer of the cell surface-directed plasmin inhibitor ATF.BPTI.Gene Ther.2001 Apr; 8(7):534-41.
[108]Ascher E, Scheinman M, Hingorani A, et al.Effect of p53 gene therapy combined with CTLA4lg selective immunosuppression on prolonged neointima formation reduction in a rat model.Ann Vasc Surg.2000 Jul; 14(4):385-92.
[109]Kitazume H, Kubo I, Iwama T,et al. Long-term angiographic follow-up of lesions patent 6 months aftecpercutaneous coronary angioplasty [J]. Am Heart J,1995,129(3): 441-444.
[110]Gibbons GH, Dzau VJ. The emerging concept of vascular remodeling. N Engl J Med.1994; 330:1431-1438.
[111]Braun-Dullaeus RC, Mann MJ, Dzau VJ. Cell cycle progression:new therapeutic target for vascular proliferative disease. Circulation.1998; 98:82-89.
[112]Sousa JE, Costa MA, Abizaid AC, RensingBJ, Abizaid AS, Tanajura LF, Kozuma K, Van Langenhove G, Sousa AG, Falotico R, Jaeger J, Popma JJ, Serruys PW. Sustained suppression of neointimal proliferation by sirolimus-eluting stents:one-year angiographic and intravascular ultrasound follow-up. Circulation.2001; 104:2007-2011
[113]Tanabe K, Degertekin M, Regar E, Ligthart JM, van der Giessen WJ, Serruys PW. No delayed restenosis at 18 months after implantation of sirolimus-eluting stent. Catheter Cardiovasc Int.2002; 57:65-68
[114]Saia F, Lemos PA, Sianos G, Degertekin M, Lee CH, Arampatzis CA, Hoye A, Tanabe K, Regar E, van der Giessen WJ, Smits PC, de Feyter P, Ligthart J, van Domburg RT, Serruys PW. Effectiveness of sirolimus-eluting stent implantation for recurrent in-stent restenosis after brachytherapy. Am J Cardiol.2003:92:200-203.
[115]Gingras AC, Raught B, Sonenberg N. Regulation of translation initiation by FRAP/mTOR. Genes Dev.2001; 15:807-826.
[116]Rameh LE, Cantley LC. The role of phosphoinositide 3-kinase lipid products in cell function. J Biol Chem.1999; 274:8347-8350.
[117]Shigematsu K, Koyama H, Olson NE, Cho A, Reidy MA. Phosphatidylinositol 3-kinase signaling is important for smooth muscle cell replication after arterial injury. Arterioscler Thromb Vasc Biol.2000; 20:2373-2378.
[118]Zhou RH, Lee TS, Tsou TC, Rannou F, Li YS, Chien S, Shyy JY. Stent implantation activates Akt in the vessel wall:role of mechanical stretch in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol.2003; 23:2015-2020.
[119]Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem.1998; 273:13375-13378.
[120]Malemud CJ.Matrix metalloproteinases(MMPs)in health and disease:an overview[J].Front Biosci,2006,11:1696-1701
[121]Aoyagi M, Yamamoto M, Azuma H, et al.Immunolocalization of matrix metalloproteinases in rabbit carotid arteries after balloon denudation[J].Histochem Cell Biol, 1998,109(2):97-102.
[122]Moon SK, Kim HM, Kim CH. PTEN induces G1 cell cycle arrest and inhibits MMP-9 expression via the regulation of NF-kappaB and AP-1 in vascular smooth muscle cells. Arch Biochem Biophys.2004; 421:267-276.
[123]Weng LP, Brown JL, Eng C. PTEN coordinates G(1) arrest by down-regulating cyclin D1 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a breast cancer model. Hum Mol Genet.2001; 10:599-604.
[124]Sun H, Lesche R, Li DM, Liliental J, Zhang H, Gao J, Gavrilova N, Mueller B, Liu X, Wu H. PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway. Proc Natl Acad Sci U S A.1999; 96:6199-6204.
[125]Cantley LC, Neel BG. New insights into tumor suppression:PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A,1999; 96:4240-4245.
[126]Sata M, Tanaka K, Ishizaka N, Hirata Y, Nagai R. Absence of p53 Leads to Accelerated Neointimal Hyperplasia After Vascular Injury. Arterioscler Thromb Vasc Biol. 2003; 23:1548-1552
[127]Vazquez F, Ramaswamy S, Nakamura N, Sellers WR. Phosphorylation of the PTEN tail regulates protein stability and function. Mol Cell Biol.2000; 20:5010-5018
[128]Vazquez F, Grossman SR, Takahashi Y, Rokas MV, Nakamura N, Sellers WR. Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex. J Biol Chem.2001; 276:48627-48630.
[129]Torres J, Pulido R. The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome- mediated degradation. J Biol Chem.2001; 276:993-998.
[130]Torres J, Rodriguez J, Myers MP, Valiente M, Graves JD, Tonks NK, Pulido R. Phosphorylation-regulated cleavage of the tumor suppressor PTEN by caspase-3: implications for the control of protein stability and PTEN-protein interactions. J Biol Chem. 2003; 278:30652-30660.
[131]Lee SR, Yang KS, Kwon J, Lee C, Jeong W, Rhee SG. Reversible inactivation of the tumor suppressor PTEN by H2O2. J Biol Chem.2002; 277:.20336-20342.
[132]Wu W, Wang X, Zhang W, Reed W, Samet JM, Whang YE, Ghio AJ. Zinc-induced PTEN protein degradation through the proteasome pathway in human airway epithelial cells. J Biol Chem.2003; 278:28258-28263.