摘要
目的:1、研究人血浆UII浓度与冠状动脉病变程度的关系。
2、通过大鼠胸主动脉球囊拉伤模型来观察损伤部位UII的表达及外源性应用UII对于损伤后重塑的影响,及能否通过UII拮抗剂Urantide拮抗内源性UII的作用。
3、离体研究不同浓度UII对大鼠拉伤血管胶原的合成与分泌的影响。
方法:1、在100名已知或怀疑冠心病患者中行冠脉造影检查,计算Micheal评分并测量血中UII浓度。
2、采用大鼠胸主动脉球囊拉伤模型,假拉伤为对照,术后持续皮下渗透泵给予UII(1nmol/kg/h)或UII拮抗剂Urangtide(10nmol/kgh)21d,检测血管形态改变、UII及受体表达、胶原含量及分型、MMP-1蛋白和MMP-2/TIMP-2比。
3、大鼠胸主动脉球囊拉伤术后7d,14d组行血管孵育,~3H-Pro掺入研究不同浓度UII对胶原的合成与分泌的影响。
结果:1、血浆UII浓度在冠脉正常或极轻微病变组(评分＜3)与冠脉病变严重组(评分≥9)间有显著差异(1.61±1.05ng/ml vs 2.50±1.62ng/ml,P=0.03)。血浆UII浓度与冠状动脉病变评分正相关,(r=0.213,P=0.034),是继年龄、血糖异常、高血压之后的独立危险因素。
2、与假拉伤组比,拉伤21d时损伤血管UII蛋白表达明显增加,UII受体GPR-14mRNA上调。予UII后损伤血管GPR-14mRNA进一步上调40%,增生内膜面积明显增加((13±5)%vs(7±2)%,P＜0.05),胶原含量增加,其中Ⅰ型胶原增加1倍,MMP-1蛋白的表达下降59.9%,MMP-2活性升高,TIMP-2蛋白减少。予Urantide后损伤血管GPR-14mRNA下调45%,增生内膜面积没有减少,胶原蛋白及mRNA水平、MMP-1蛋白均无明显改变,MMP-2活性升高,TIMP-2蛋白减少。
3、UII以浓度依赖的方式刺激血管组织~3H-Pro掺入。拉伤血管对UII的反应性增强,拉伤术后7d时UII10~(-10)、10~(-9)、10~(-8)mol/l分别使胶原合成增加87.7%、81.2%和56.8%,P＜0.05;胶原分泌增加34.6%、17.5%和17.2%,P＜0.05。拉伤14d时胶原合成及分泌的增加较7d减少。
结论:1、在严重冠脉病变患者血浆中UII水平显著升高,并且UII水平与冠脉病变程度明显正相关。
2、大鼠胸主动脉损伤后局部UII的表达增强,GPR-14mRNA水平上调,外源性应用UII后GPR-14mRNA水平进一步上调,促进新生内膜胶原沉积,加重损伤血管狭窄。10nmol/kg/h的Urantide能抑制GPR-14mRNA水平上调,但对胶原沉积无明显影响,未能表现出拮抗血管狭窄的作用,甚至对MMP-2/TIMP-2平衡有类UII的作用,其意义有待进一步研究。
Objectives:1.To study the correlation between UrotensinⅡ(UⅡ) concentration and the severity of coronary artery disease(CAD).
2.To evaluate the exogenous UII's effection on injured vessel,especially the extracellular matrix response.In addition the effect of Urantide,a selective peptidic UT receptor antagonist,was assessed too.
3.To evaluate the effection of UrotensinⅡon collagen synthesis and secretion in vitro.
Methods:1.We studied UII concentrations in 100 patients with known or suspected CAD referred for coronary arteriography.Micheal score system was used to estimate the severity of CAD.
2.Stenosis model of thoracic aorta 21 days after balloon injury was established in male Wistar rats,which were divided into 4 groups(n=5),including sham injured,injured,UII(1nmol/kg/h,infused by osmotic mini-pump) and Urantide(10nmol/kg/h) group.H-E staining and Masson-Trichrome staining were used for morphometric analysis,RT-PCR for the mRNA expressions and immunohistochemical staining assay for protein expression.
3.Thoracic aortas were separated 7days and 14 days after balloon injury(4 rats per group) and treated with UrotensinⅡ,collagen synthesis and secretion were measured by ~3H-proline incorporation.
Results:1.UII concentration was higher in severer group(score≥9) than in normal or nearly normal group(score＜3),(2.50±1.62ng/ml vs 1.61±1.05ng/ml,P=0.03) UII concentration correlated with CAD severity(r=0.213,P=0.034).By multiple regression analysis,UII is one determinant of the severity of CAD,other than age, abnormal glucose,hypertension and gender.
2.①Compared with sham injured vessel,UII was increased significantly in injured vessel,and GRP-14mRNA was upregulated.②In UII group GRP-14mRNA further upregulated,the intimal hyperplasia was markedly increased((13±5)%vs (7±2)%,P＜0.05),collagen content was also increased,typeⅠcollagen increased 1 fold,typeⅢcollagen decreased 64%,while no significant difference in mRNA levels was found.MMP-1 decreased significantly(3.33±0.82 vs 8.30±1.81,P＜0.05). MMP-2 activity increased 1.25 fold,TIMP-2 protein decreased by 73.3%.③In Urantide group,compared with injured group,GRP-14mRNA dowuregulated,the intimal hyperplasia didn't reduce((9±3)%vs(7±2)%,P＞0.05),collagen protein and mRNA had no difference,MMP-1 protein had no significant difference,the activity of MMP-2 increased 1.29 fold,TIMP-2 protein decreased by 55.4%.
3.UII stimulated the collagen synthesis in non-injured vessel in a concentration-dependent manner.In aorta 7days after balloon injury,the collagen synthesis increased by 87.7%,81.2%,56.8%(all P＜0.05) than in non-injured vessel stimulated by 10~(-10),10~(-9) and 10~(-8)mol/l UII respectively,and collagen secretion increased by 34.6%,17.5%and 17.2%(all P＜0.05).The synthesis and secretion increase 14 days later is less than that of 7days later.
Conclusions:1.UII is elevated in severe CAD and there is a significant relationship between UII concentration and CAD severity.
2.In injured vessel,UII expression increases,and GRP-14 mRNA upregulates.Exogenous UII stimulates GRP-14 mRNA upregulation,collagen accumulation,and increases MP-2/TIMP-2 rate which may prolong vascular remodeling contributing to intimal hyperplasia.Urantide(10nmol/kg/h) can antagonize GRP-14mRNA upregulation,but has no effect on collagen accumulation and has a similar tendency on MMP-2/TIMP-2 balance,so in present study,Urantide has no protective effect on blood vessel stenosis.
引文
1.Pasterkamp G,Kleijn D,Borst C.Arterial remodeling in atherosclerosis,restenosis and after alteration of blood flow:potential mechanisms and clinical implications.Cardiovascular Research 2000;45:843-852.
2.Strauss BH,Chisholm RJ,Keeley FW,et al.Extracellular matrix remodeling after balloon angioplasty injury in a rabbit model of restenosis.Circ Res 1994;75:650-658.
3.任冰稳,马爱群。动脉粥样硬化与基质金属蛋白酶。心血管病学进展2003;24(1):47-52。
4.Ames RS,Sarau HM,Chambers JK,et al.Human urotensin Ⅱ is a potent vasoconstrictor and agonist for the orphan receptor GPR14.Nature 1999;401:282-286.
5.Takanobu Y,Mika M,Yukio H.Role of urotensin Ⅱ in peripheral tissue as an autocrine/paracrine growth factor.Peptides 2004;25:1775-1781.
6.Shi L,Ding W,Li D,et al.Proliferation and anti-apoptotic effects of human urotensin Ⅱ on human endothelial cells.Atherosclerosis 2006;188(2):260-264.
7.Watanabe T,Suguro T,Kanome T,et al.Human urotensin Ⅱ accelerates foam cell formation in human monocyte-derived macrophages.Hypertension 2005;46(4):738-744.
8.Wang H,Mehta JL,Chen K,et al.Human urotensin Ⅱ modulates collagen synthesis and the expression of MMP-1 in human endothelial cells.J Cardiovasc Pharmacol 2004;44(5):577-581.
9.Hassan GS,Douglas SA,Ohlstein EH,et al.Expression of urotensin-Ⅱ in human coronary atherosclerosis.Peptide 2005;26(12):2464-2472.
10.Ewa R,Ghada SH,Dashyant D,et al.A role for urotensin Ⅱ in restenosis following balloon angioplasty:use of a selective UT receptor blocker.J Mol Cell Cardiol 2005;39:785-791.
11.夏春芳,徐少平,张勇刚等。大鼠主动脉球囊成形术后尾加压素Ⅱ受体的变化。中国病理生理杂志 2001;17(7):593-597。
12.Micheal FR,Paul JN,Ian HC,et al.Lipoprotein predictors of the severity of coronary artery disease in men and women.Circulation 1985;71(5):881-888.
13.Deckers JW,Goedhart DM,Boersma E,et al.Treatment benefit by perindopril in patients with stable coronary artery disease at different levels of risk.Eur Heart J 2006;27(7):796-801.
14.Cickroft DW,Gault MH.Prediction of creatinine clearance from serum creatinine.Nephron 1976;16:31-41.
15.Heringlake M,Kox T,Uzun O,et al.The relationship between urotensin Ⅱplasma immunoreactivity and left ventricular filling pressures in coronary artery disease.Regul Pept 2004;121:129-136.
16.方石虎,李志樑,吴宏超等。冠心病患者血浆尾加压素Ⅱ的临床研究。第一军医大学学报 2004;24(5):563-565。
17.Joyal D,Huynh T,Aiyar N,et al.Urotensin-Ⅱ levels in acute coronary syndromes. Int J Cardiol 2006;108(1):31-35.
18.史力斌,丁文惠,杨俊娟等。缺血性心脏病患者血浆尾加压素Ⅱ水平的变化及意义。中华内科杂志 2001:40(9):634-635。
19.Gensini GG.A more meaningful scoring system for determining the severity of coronary heart disease.The American Journal of Cardiology,1983;51(3):606-610.
20.Katano Y,Ishihata A,Aita T,et al.Vasodilator effect of urotensin Ⅱ,one of the most potent vasoconstricting factors,on rat coronary arteries.Eur J Pharmacol 2000;402:209-211.
21.Lim M,Honisett S,Sparkes CD,et al.Differential effect of urotensin Ⅱ on vascular tone in normal subjects and patients with chronic heart failure.Circulation 2004;109(10):1212-1214.
22.Sohail QK,Sanjay SB,Paulene Q,et al.Urotensin Ⅱ is raised in acute myocardial infarction and low levels predict risk of adverse clinical outcome in humans.Int J Cardiol 2007;117:323-328.
23.Richards M,Nicholls G,Lainchbury JG,et al.Plasma urotensin Ⅱ in heart failure.The Lancet 2002;360(9332):545-546.
24.CheungBM Y,Leung R,Man Y B,et al.Plasma concentration of urotensin Ⅱ is raised in hypertension.J Hypertens 2004;22:1341-1344.
25.Totsune K,Takahashi K,Arihara Z,et al.Role of urotensin Ⅱ in patients on dialysis.Lancet 2001;358:774-775.
26.Thompson,J P,Watt,P,Sanghavi,S,et al.A comparison of cerebrospinal fluid and plasma urotensin Ⅱ concentrations in normotensive and hypertensive patients undergoing urological surgery during spinal anesthesia:a pilot study.Anesth Analg 2003;97:1501-1503.
27.Totsune K,Takahashi K,Arihara Z,et al.Increased plasma urotensin Ⅱ levels in patients with diabetes mellitus.Clin Sci(Lond).2003 Jan;104(1):65-67.
28.Bartnik M,Ryden L,Ferrari R,et al.The prevalence of abnormal glucose regulation in patients with coronary disease across Europe:the Euro Heart Survey on diabetes and the heart.Eur Heart J 2004;25:1880-1890.
29.Toshiaki S,Takuya W,Yoshiyuki B,et al.Increased human Urotensin Ⅱ levels are correlated with carotid atherosclerosis in essential hypertension.Am J Hypertens 2007;20:211-217.
30.程虹,田雪飞,董鸿瑞等。依那普利及波生坦对糖尿病肾病大鼠干预作用的初步研究。中华糖尿病杂志2004;12(6)437-441。
31.Daemen MJ,Lombardi DM,Bosman FT,et al.Angiotensin Ⅱ induces smooth muscle cell proliferation in the normal and rat arterial wall.Circ Res 1991;68(2):450-456.
32.龚志锦,詹容洲主编。病理组织制片和染色技术。第1版,上海:上海科学技术出版社,1994:61。
33.纪小龙,施作霖主编。诊断免疫组织化学。第1版,北京:军事医学科学出版社,1997:248。
34.于萍,步宏,王华等。免疫组化结果的图像分析与人工计数方法的对比研究。生物医学工程学杂志 2003;20(2):288-290。
35.Godin D,Ivan U,Johnson C,et al.Remodeling of carotid artery is associated with increased expression of matrix metalloproteinases in mouse blood flow cessation model.Circulation 2000;102:2861.
36.Ick-Mo Chung.The role of extracellular matrix in restenosis after percutaneous coronary intervention.International Congress Series 2004;1262:414-417.
37.Zorina S G,Jaikirshan J K.Matrix metalloproteinases in vascular remodeling and atherogenesis The good,the bad,and the ugly.Circulation Research 2002;90:251-262.
38.Shi Y,O'Brien J E,Fard A,et al.Adventitial myofibroblasts contribute to neointimal formation in injured porcine coronary arteries.Circulation 1996;94:1655-1664.
39.Shi Y,O'Brien JE,Kokko LA,et al.Origin of extracellular matrix synthesis during coronary repair.Circulation 1997;95:997-1006.
40.Mason DP,Kenagy RD,Hasenstab D,et al.Matrix metalloproteinase-9 overexpression enhances vascular smooth muscle cell migration and alters remodeling in the injured rat carotid artery.Circ Res,1999;85(12):1179-1185.
41.Uzui H,Lee JD,Shimizu H,et al.The role of protein-tyrosine phosphorylation and gelatinase production in the migration and proliferation of smooth muscle cells.Atherosclerosis 2000;149(1):51-59.
42.Kompaa AR,Thomasb WG,Seea F.Cardiovascular role of urotensin Ⅱ:effect of chronic infusion in the rat.Peptides 2004;25:1783-1788.
43.Rizvim AD,Katwa L,Spadone DP et al.The effects of endothelin-1 on collagen type Ⅰ and type Ⅲ synthesis in cultured porcine coronary artery vascular smooth muscle cells.J Mol Cell Cardiol 1996;28:243-252.
44.Mohammed AD,Rizvi,Paul RM.Nitric Oxide modulates basal and endothelininduced coronary artery vascular smooth muscle cell proliferation and collagen levels.J Mol Cell Cardiol 1997;29:1779-1789.
45.杨季明,陈磊磊,王迪斌等。兔髂动脉内皮损伤后缬沙坦对转化生长因子β1和Ⅰ型胶原表达的影响。南京医科大学学报2003;4:395-397。
46.张丽芳,柯元南。动脉内膜损伤后血管重塑相关因子的动态变化。中日友好医院学报 2007;2:91-93
47.Alan WB,Saeid B,Ranga R,et al.Administration of exogenous endothelin-1following vascular balloon injury:early and late effects on intimal hyperplasia.Cardiovascular Research 2001;52:468-476.
48.Gibson A.Complex effects of Gillichthys urotensin Ⅱ on rat aortic strips.Br J Pharmacol 1987;91:205-212.
49.Ewa Rakowski,Ghada SH,Dashyant D.A role for urotensin Ⅱ in restenosis following balloon angioplasty:use of a selective UT receptor blocker.J Mol Cell Cardiol 2005;39:785-791.
50.Sidharta PN,Wagner FD,Bohnemeier H,et al.Pharmacodynamics and pharmacokinetics of the urotensin Ⅱ receptor antagonist palosuran in macroalbuminuric diabetic patients.Clin Pharmacol Ther 2006;80(3):246-56.
51.郑丽丽,李成光,傅向华等。转化生长因子βⅡ型受体在糖尿病大鼠血管损伤后的表达及氯沙坦对其调节作用。中华心血管病杂志2003;31(4):285-288。
52. Bradley H S, Robert J C, Fred W K, et al. Extracellular matrix remodeling after balloon angioplas injury in a rabbit model of restenosis. Circ Res. 1994; 75: 650-658.
53. Huang HC, Ma CY, Yang M, et al.Adrenomedullin impairs the profibrotic effects of transforming growth factor-|3l through recruiting smad-2 protein in human renal tubular cells. Cell Physiol Biochem 2005; 15:117-124.
54. Pasterkamp G, Kleijn D, Borst C. Arterial remodeling in atherosclerosis, restenosis and after alteration of blood flow: potential mechanisms and clinical implications. Cardiovascular Research 2000;45: 843-852.
1.Coulouarn Y,Lihrmann I,Jegou S,et al.Cloning of the cDNA encoding the urotensin Ⅱ precursor in frog and human reveals intense expression of the urotensin Ⅱ gene in motoneurons of the spinal cord.Proc Natl Acad Sci U S A 1998:95:15803-15808.
2.Ames R S,Sarau H M,Chambers J K,et al.Human urotensin Ⅱ is a potent vasoconstrictor and agonist for the orphan receptor GPR14.Nature 1999;401:282-286.
3.George T,Thao H,Adel G.Urotensin Ⅱ and cardiovascular diseases.Peptides 2004;25:1789-1794.
4.Takanobu Y,Mika M,Yukio H.Role of urotensin Ⅱ in peripheral tissue as an autocrine/paracrine growth factor.Peptides 2004;25:1775-1781.
5.Shi L,Ding W,Li D,et al.Proliferation and anti-apoptotic effects of human urotensin Ⅱ on human endothelial cells.Atherosclerosis 2006:188(2):260-264.
6.Watanabe T,Suguro T,Kanome T,etal.Human urotensin Ⅱ accelerates foam cell formation in human monocyte-derived macrophages.Hypertension 2005;46(4): 738-744.
7. Wang H, Mehta JL, Chen K, et al. Human urotensin II modulates collagen synthesis and the expression of MMP-1 in human endothelial cells. J Cardiovasc Pharmacol 2004;44(5):577-581.
8. Tzanidis A, Hannan RD, Thomas WG, et al. Direct actions of urotensin II on the heart: implications for cardiac fibrosis and hypertrophy. Circ Res 2003;93:246-253.
9．夏春芳,徐少平,张勇刚等。大鼠主动脉球囊成形术后尾加压素II受体的变化。中国病理生理杂志2001；17(7)：593-597。
10. Nakayama K. Furin: a mammalian subtilisin/Kex2p-like endoprotease involved in processing of a wide variety of precursor proteins. Biochem J 1997;327:625- 635.
11. Denault JB, Claing A, D'Orle'ans-Juste P, et al. Processing of proendothelin-1 by human furin convertase. FEBS Lett 1995;362: 276- 280.
12. Di Napoli P, Taccardi AA, Grilli A, et al. Proparathyroid hormone is preferentially cleaved to parathyroid hormone by the prohormone convertase furin. J Biol Chem 1995;270: 9517-9525.
13. Maguire JJ, Kuc RE, Davenport AP. Orphan-receptor ligand human urotensin II: receptor localization in human tissues and comparison of vasoconstrictor responses with endothelin-1. Br J Pharmacol 2000; 131:441-446.
14. Matsushita M, Shichiri M, Fukai N, et al. Urotensin II is an autocrine/paracrine growth factor for the porcine renal epithelial cell line, LLCPK1. Endocrinology 2003; 144:1825-1831.
15. Matsushita M, Shichiri M, Imai T, et al. Co-expression of urotensin II and its receptor (GPR14) in human cardiovascular and renal tissues. J Hypertens 2001; 19: 2185-2190.
16. Nothacker HP, Wang Z, McNeill AM, et al. Identification of the natural ligand of an orphan G-proteincoupled receptor involved in the regulation of vasoconstriction. Nat Cell Biol 1999;1:383-385.
17. Pearson D, Shively JE, Clark BR, et al. Urotensin II-induced activation of extracellular signalregulated kinase in cultured vascular smooth muscle cells: involvement of cell adhesion-mediated integrin signaling. Life Sci 2003;72:1049-1060.
18. Totsune K, Takahashi K, Arihara Z, et al. Role of urotensin II in patients on dialysis. Lancet 2001;358:810-811.
19. Douglas SA, Sulpizio AC, Piercy V, et al. Differential vasoconstrictor activity of the human urotensin-II in vascular tissue isolated from the rat, mouse, dog, pig, marmoset and cynomolgus monkey. Br J Pharmacol 2000; 131:1262-274.
20. Maguire JJ, Kuc RE, Davenport AP. Orphan-receptor ligand human urotensin II: receptor localization in human tissues and comparison of vasoconstrictor responses with endothelin-1. Br J Pharmacol 2000;131:441- 446.
21. Camarda V, Rizzi A, Calo' G, et al. Effects of human urotensin II in isolated vessels of various species; comparison with other vasoactive agents. Naunyn Schmiedeberg' s Arch Pharmacol 2002;365:141-149.
22. Douglas SA, Ashton DJ, Sauermelch CF, et al. Human urotensin-II is a potent vasoactive peptide: pharmacological characterization in the rat, mouse, dog and primate. J Cardiovasc Pharmacol 2000;36(Suppl. 1): S163- S166.
23. Hillier C, Berry C, Petrie M C, et al. Effects of urotensin II in human arteries and veins of varying caliber. Circulation 2001;103:1378-1381.
24. Stirrat A, Gallagher M, Douglas S A, et al. Potent vasodilator responses to human urotensin-II in human pulmonary and abdominal resistance arteries. Am J Heart Circ Physiol 2001 ;280: H925- H928.
25. Gibson A. Complex effects of Gillichthys urotensin II on rat aortic strips. Br J Pharmacol 1987;91:205-212.
26. Katano, Y, Ishihata, A, Aita, T, et al. Vasodilator effect of urotensin II, one of the most potent vasoconstricting factors, on rat coronary arteries. Eur J Pharmacol 2000;402:209-211.
27. Gardiner S M, March J E, Kemp P A, et al. Depressor and regionally-selective vasodilator effects of human and rat urotensin II in conscious rats. Br J Pharmacol 2001; 132:1625-1629.
28. Bottrill F E, Douglas S A, Hiley C R, et al. Human urotensin-II is an endothelium-dependent vasodilator in rat small arteries. Br J Pharmacol 2000; 130: 1865- 1870.
29. Zhang AY, Chen YF, Zhang DX, et al. Urotensin II is a nitric oxide-dependent vasodilator and natriuretic peptide in the rat kidney. Am J Physiol Renal Physiol 2003;285:F2792-F2798.
30. Leslie S J, Denvir M, Webb DJ. Human urotensin II causes vasoconstriction in the human skin microcirculation. Circulation 2000;102(Suppl. II): 110-113.
31. Bfhm F, Pernow J. Urotensin II evokes potent vasoconstriction in humans in vivo. Br J Pharmacol 2002; 135:25- 27.
32. Wilkinson I B, Affolter J T, de Haas S L, et al. High plasma concentrations of human urotensin II do not alter local or systemic hemodynamics in man Cardiovasc Res 2002;53: 341-347.
33. Sondermeijer B, Kompa A, Komesaroff P. Effect of exogenous urotensin-II on vascular tone in skin microcirculation of patients with essential hypertension. Am J Hypertens 2005;18: 1195-1199.
34. Lim M, Honisett S, Sparkes CD, et al. Differential effect of urotensin II on vascular tone in normal subjects and patients with chronic heart failure. Circulation 2004 ; 109(10): 1212-1214.
35. Russell FD, Molenaar P, O'Brien DM. Cardiostimulant effects of urotensin-II in human heart in vitro. Br J Pharmacol 2001; 132: 5-9.
36. Burrell K M, Molenaar P, Dawson PJ, et al.Contractile and arrhythmic effects of endothelin receptor agonists in human heart in vitro: blockade with SB 209670. J Pharmacol Exp Ther 2000;292:449- 459.
37. Douglas A,Tayara L,Ohistein H, et al. Congestive heart failure and expression of myocardial urotensin II. Lancet 2002;359:1990-1997.
38. Richard A, Nicholls M, Jainchbury G, et al. Plasma urotensin II in heart failure. Lancet 2002;360:545-546.
39. Sauzeau V, Le Mellionec E, Bertoglio J, et al. Human urotensin II-induced contractio n and arterial smooth muscle cell proliferation are mediated by RhoA and Rhokinase. Circ Res 2001;88:1102-1104.
40. Watanabe T, Pakala R, Katagiri T, et al. Synergistic effect of urotensin II with serotonin on vascular smooth muscle cell proliferation. Journal of Hypertension 2001;19:2191-2196.
41. Watanabe T, Pakala R, Katagiri T, et al. Synergistic effect of urotensin II with mildly oxidized LDL on DNA synthesis in vascular smooth muscle cells. Circulation 2001;104:16-18.
42.张勇刚,陈亚红,马春艳等。尾加压素Ⅱ的促丝裂作用。中国动脉硬化杂志2001:9(1):14-17。
43.张勇刚,齐永芬,夏春芳等。尾加压素Ⅱ对血管平滑肌细胞增殖的影响。中国药理学通报2001:17(2):155-157。
44.动脉粥样硬化。内科学,人民卫生出版社,第五版,2001:272-273。
45.Post MJ,Borst C,Kuntz RE.The relative importance of arterial remodeling compared with intimal hyperplasia in lumen renarrowing after balloon angioplasty.Circulation 1994;89:2816-2821.
46.Gutterman DD.Adventitia-dependent influences on vascular function.Am J Physiol 1999;277:H1265-1272.
47.Sartoe S,Chiavegato A,Faggin E,et al.Contribution of adventitial fibroblasts to neointima formation and vascular remodeling:from innocent bystander to active participant.Circ Res 2001;89(12):1111-1121.
48.Zalewski A,Shi y.Vascular myofibroblasts.Lessons from coronary repair and remodeling.Arterioscler Thromb Vasc Biol 1997;17(3):417-422.
49.Wang ZJ,Shi LB,Xiong ZW,et al.Alteration of vascular urotensin Ⅱ receptor in mice with apolipoprotein E gene knockout.Peptides 2006;27(4):858-863.
50.Gendron G,Simard B,Gobeil F,et al.Human urotensin-Ⅱ enhances plasma extravasation in specific vascular districts in Wistar rats.Can J Physiol Pharm 2004;82:16-21.
51.Totsune K,Takahashi K,Arihara Z,et al.Increased plasma urotensin Ⅱ levels in patients with diabetes mellitus.Clin Sci 2003;104:1-5.
52.Silvestre R A,Rodry'guez-Gallardo J,Egido E M,et al.Inhibition of insulin release by urotensin Ⅱ—a study on the perfused rat pancreas.Horm Metab Res 2001;33:379-381.
53.Wenyi Z,Suzuki S,Hirai M,et al.Role of urotensin Ⅱ gene in genetic susceptibility to type 2 diabetes mellitus in Japanese subjects.Diabetologia 2003;46:972-976.
54.Heringlake M,Kox T,Uzun O,et al.The relationship between urotensin Ⅱ plasma immunoreactivity and left ventricular filling pressures in coronary artery disease.Regul Pept 2004;121(1-3):129-136.
55.Joyal D,Huynh T,Aiyar N,et al.Urotensin-Ⅱ levels in acute coronary syndromes.Int J Cardiol 2006;108(1):31-35.
56.Behm DJ,Herold CL,Ohlstein EH,et al.Pharmacological characterization of SB-710411(Cpa-c[D-Cys-Pal-D-Trp-Lys-Val-Cys]-Cpa-amide),a novel peptidic urotensin-Ⅱ receptor antagonist.Br J Pharmacol 2002;137:449-458.
57.Camarda V,Guerrini R,Kostenis E,et al.A new ligand for the urotensin Ⅱ receptor.Br J Pharmacol 2002;137:311-314.
58.Herold CL,Behm DJ,Buckley PT,et al.The neuromedin B receptor antagonist,BIM-23127,is a potent antagonist at human and rat urotensin-Ⅱ receptors.Br J Pharmacol.2003;139:203-207.
59.Riccardo P,Paolo S,Sandro G,et al.Urantide:an ultrapotent urotensin Ⅱ antagonist peptide in the rat aorta.Br J Pharmacol 2003;140:1155-1158.
60.Camarda V,Song W,Marzola,etal.Urantide mimics urotensin-Ⅱ induced calcium release in cells expressing recombinant UT receptors.Eur J Pharmacol 2004;498:83-86
61.Dhanak D,Knight SD.Sulfonamide derivative urotensin-Ⅱ receptor antagonists,preparation,pharmaceutical compositions,and therapeutic use.PCT Int Appl 2001;(WO 2001045694).
62.Ewa Rakowski,Ghada S H,Dashyant D.A role for urotensin Ⅱ in restenosis following balloon angioplasty:use of a selective UT receptor blocker.Journal of Molecular and Cellular Cardiology 2005;39:785-791.
63.Sidharta PN,Wagner FD,Bohnemeier H,et al.Pharmacodynamics and pharmaco kinetics of the urotensin Ⅱreceptor antagonist palosuran in macroalbuminuric diabetic patients.Clin Pharmacol Ther 2006;80(3):246-56.
64.Alan WB,Saeid B,Ranga R,et al.Administration of exogenous endothelin-1 follow ing vascular balloon injury:early and late effects on intimal hyperplasia.Cardio vasc Research 2001;52:468-476
65.杨季明,陈磊磊,王迪斌等。兔髂动脉内皮损伤后缬沙坦对转化生长因子β1和Ⅰ型胶原表达的影响。南京医科大学学报 2003;4:395-397。
66.郑丽丽,李成光,傅向华等。转化生长因子βⅡ型受体在糖尿病大鼠血管损伤后的表达及氯沙坦对其调节作用。中华心血管病杂志2003;31(4):285-288。
67.Watanabe T,Kanome T,Miyazaki A,et al.Human Urotensin Ⅱ as a link between hypertension and coronary artery disease.Hypertens Res 2006;29:375-387.
1.Pasterkamp G,Schoneveld AH,Hijien DJ,et al.Atherosclerotic arterial remodeling and the location of macrophages and matrix metalloproteases1,2 and 9 in the human coronary artery.Atherosclerosis 2000;150:245-253.
2.Sukhova GK,Schonbeck U,Rabkin E,et al.Evidance for increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques.Circulation 1999;,99:2503-2509.
3.de Smet BJGL,Pasterkamp G,van der Helm YJ,et al.The relation between de novo atherosclerotic remodeling and angioplasty-induced remodeling in an atherosclerotic yucatan micropig model.Arterioscl Thromb Vasc Biol 1998;188:702-707.
4.Kimura T,Kaburagi S,Tamura T,et al.Remodeling of human coronary arteries undergoing coronary arterial angioplasty or atherectomy.Circulation 1997;96:475-483.
5.Post MJ,Borst C,Kuntz RE.The relative importance of arterial remodeling compared with intimal hyperplasia in lumen renarrowing after balloon angioplasty. Circulation 1994;89:2816-2821.
6. Jia X, Huo Y, Zhu G. Relationship of vascular remodeling and restenosis after interventional therapy: an experimental study on rabbit atherosclerotic iliac artery model. Chin Med J 1999 ; 112 (5) :400.
7. NAsahara T, Bauters C, Pastore C. Local delivery of vascular endothelial growth factor accelerates reendothelialization and attenuates intimal hyperplasia in balloon-injured rat carotid artery. Circulation 1995;91:2793-2801.
8. Fukumoto Y, Shimokawa H, Kozai T, et al. Tyrosine kinase inhibitor suppresses the (re)stenotic changes of the coronary artery after balloon injury in pigs. Cardiovascular Res 1996;32:1131-1140.
9. Smith JD, Bryant SR, Couper LL, et al. Soluble transforming growth factor b type II receptor inhibits negative remodeling, fibroblast transdif-ferentiation and intimal lesion formation but not endothelial growth. Circ Res 1999;84: 1212-1222.
10. Schwarzacher SP, Lim TT, Wang B, et al. Local intramural delivery of L-arginine enhances nitric oxide generation and inhibits lesion formation after balloon angioplasty. Circulation 1997;95:1863-1869.
11. Varenne O, Pislaru S, Gillijns H, et al. Local adenovirus-mediated transfer of human endothelial nitric oxide synthase reduces luminal narrowing after coronary angioplasty in pigs. Circulation 1998;98:919-926.
12. Brownlee and Langille. Arterial adaptations to altered blood flow. Can J Physiol Pharmacol. 1991;69(7):978-983.
13. Krams R, Wentzel JJ, Oomen JAF, et al. Shear stress in atherosclerosis, and vascular remodelling. Semin Intervent Cardiol 1998;3:39-44.
14. Bassiouny HS, Song RH, Hong XF, et al. Flow regulation of 72-kD collagenase IV (MMP-2) after ex-perimental arterial injury. Circulation 1998;98:157-163.
15. De Kleijn D, Velema E, Schoneveld A, et al. Increase of metalloproteinase-2 and -9 activity during flowinduced remodeling is regulated at the post transcriptional level. JAm Coll Cardiol 1999;33 Suppl:268A.
16. Pasterkamp G, Kleijn D, Borst C. Arterial remodeling in atherosclerosis, restenosis and after alteration of blood flow: potential mechanisms and clinical implications. Cardiovascular Research 2000;45: 843-852.
17. Gutterman DD. Adventitia-dependent influences on vascular function. Am J Physiol 1999;277:H1265-1272.
18. Sartoe S, Chiavegato A, Faggin E, et al. Contribution of adventitial fibroblasts to neointima formation and vascular remodeling: from innocent bystander to active participant. Circ Res 2001;89(12):1111-1121.
19. Zalewski A, Shi y. Vascular myofibroblasts: Lessons from coronary repair and remodeling. Arterioscler Thromb Vasc Biol 1997;17(3):417-422.
20. Shi y, O'Brien JE, Fard A, et al. Adventitial myofibroblasts contribute to neointimal formation in injured porcine coronary arteries. Circulation 1996;94(7): 1655-1664.
21. Siow RC, Mallawaarachchi CM, Weissberg PL. Migration of adventitial myofibroblasts following vascular ballon injury: insights from in vivo gene transfer to rat carotid arteries. Cardiovasc Res 2003;59(1):212-221.
22. Stenmark KR, Gerasimovskaya E, Nemenoff RA, et al. Hypoxic activation of adventitial fibroblasts: role in vascular remodeling. Chest 2002; 122(6 Suppl): 326-334.
23. Mazur W, Ali MN, Khan M, et al. High dose rate intracoronary radiation for inhibition of neointimal formation in the stented and balloon injured porcine models of restenosis: angiographic,morphometric and histopathologic analyses. Int J Radiation Oncology Biol Phys 1996;36:777-788.
24. Waksman R, Rodriguez JC, Robinson KA, et al. Effect of intravascular irradiation on cell proliferation, apoptosis, and vascular remodeling after balloon overstretch injury of porcine coronary arteries. Circulation 1997;96:1944-1952.
25. Wilcox JN, Waksman R, King SB, et al. The role of the adventitia in the arterial response to angioplasty: the effect of intravascular radiation. Int J Radiation Oncology Biol Phys 1996;36:789-796.
26. Filzgerrald M, Hayward IP, Thomas AC, et al. Matrix metalloproteinase can facilitate the heparanase-induced promotion of phenotype change in vascular smooth muscle cells. Atherosclerosis 1999; 145:97-106
27. Southgate KM, Fisher M, Banning AP, etal. Upregulation of basement membrane-degrading metalloproteinase secretion after balloon injury of pig carotid arteries. Circ Res 1996;79: 1177-1187.
28. Lijnen H R, Lupu F, Moons L, et al. Temporal and topographic matrix metalloproteinase expression after vascular injury in mice. Thrombosis and Haemostasis 1999; 81(5): 799-807
29. Mark GJ, Michael TC, Claudio B, et al. Increased expression of membrane-type matrix metalloproteinase and preferential localization of matrix metallo proteinase-2 to the neointima of balloon-injured rat carotid arteries. Circulation 1998;97:82-90.
30. Masafumi K, Akihisa I. Role of matrix metalloproteinases in vascular remodeling. Atheroscler Thromb 2003;10:275-282.
31. George SJ, Lloyd CT, Angelini GD, et al. Inhibition of late vein graft neointima formation in human and porcine models by adenovirus-mediated overexpression of tissue inhibitor of metalloproteinase-3. Circulation 2000;101:296-304.
32. Guo YH, Li Q, Chen GH,et al. Adenovirus-mediated transfer of TIMP-4 gene inhibits neointimal formation after balloon injury. J Peking Univ (health Sci) 2003;35:434-437.
33. Hui B, Dang Q, Wang XF et al. Intravascular ultrasound study of coronary remodeling and determination of matrix metalloproteinase and hypersensitive C-reactive protein. Zhonghua-Xin-Xue-Guan-Bing-Za-Zhi. 2005; 33(5): 428-32.
34. Zeng B, Prasan A, Fung KC, et al. Elevated circulating levels of matrix metalloproteinase-9 and -2 in patients with symptomatic coronary artery disease. Intern-Med-J. 2005; 35(6): 331-335.
35. van-Laake LW, Vainas T, Dammers R, et al. Systemic dilation diathesis in patients with abdominal aortic aneurysms: a role for matrix metalloproteinase-9? Eur J Vasc Endovasc Surg 2005;29(4): 371-377.
36.Aarsetoy H,Brugger-Andersen T,Hetland O,et al.Long term influence of regular intake of high dose n-3 fatty acids on CD40-ligand,pregnancy-associated plasma protein A and matrix metalloproteinase-9 following acute myocardial infarction.Thromb-Haemost.2006;95(2):329-336.
37.Manginas A,Bei E,Chaidaroglou A,et al.Peripheral levels of matrix metalloproteinase-9,interleukin-6,and C-reactive protein are elevated in patients with acute coronary syndromes:correlations with serum troponin I.Clin-Cardiol.2005;28(4):182-186.
38.Jones GT,Kay IP,Chu JW,et al.Elevated plasma active matrix metalloproteinase-9 level is associated with coronary artery in-stent restenosis.Arterioscler Thromb Vase Biol.2006;26(7):e121-125.
39.李绍冰,傅向华,王春梅等。罗格列酮或氯沙坦及二者合用对大鼠血管损伤后再狭窄影响的研究。中国老年学杂志2005;25:546-548。