摘要
同型半胱氨酸(Homocysteinemia, Hcy)是人体内蛋氨酸代谢的中间产物,各种原因导致的血液中总Hcy(total Hcy, tHcy)的浓度病理性升高称为高同型半胱氨酸血症(Hyperhomocysteinemia, HHC)。很多因素可引起血浆tHcy升高,如叶酸、维生素B缺乏、各种原因导致的肾脏损伤及服用药物等。大量流行病学资料发现,HHC是人群心脑血管疾病发病的独立危险因子。慢性肾脏病(chronic kidney disease, CKD)是导致高同型半胱氨酸血症的重要原因之一,当患者肾功能水平逐渐减退至终末期肾脏病(end stage renal disease, ESRD)需要透析治疗时,超过90%的患者同时伴有中等水平的高同型半胱氨酸血症(>15μmol/L),而心脑血管病变是CKD患者的重要并发症。Moustapha等研究发现,血浆tHcy水平升高与ESRD患者心、脑血管病变发病率升高有关,血浆tHcy浓度每增加1μmol/L, CVD相对危险性增加1%。但Wald等人进行的一项荟萃分析显不tHcy每增高5μmol/L,心血管事件的危险率增高32%,脑卒中风险升高59%。按此推理,在CKD患者中高同型半胱氨酸血症发生率如此之高,心脑血管事件的危险性会出现成倍增加,而事实并非如此。所以,CKD患者的HHC是否是其高心脑血管病变发生率的危险因素以及其作用机制目前尚有争议。
血细胞来源的组织因子(TF)在病理性血栓中的作用已有广泛的研究。其中Mo TF与动脉粥样硬化的发生与发展及血栓形成有密切的关系。新近发现,AMI及不稳定性心绞痛患者外周血中Mo TF的表达明显高于稳定性心绞痛的患者,AMI发作后的持续性高凝状态与Mo的TF表达增高有关。而AIS患者凝血、抗凝及纤溶活性改变在血栓形成的发病过程中亦具有重要意义。其TF在血管内不恰当地表达引起血栓形成会导致致死性的栓塞。MoTF受多种因素影响,有报道表明Hcy能通过诱导血管内皮细胞TF的表达改变机体凝血和抗凝机制,那么Hey能否通过诱导单核细胞TF基因表达的上调从而导致CKD患者急性心脑血管血栓性疾病发病率增高,以及其诱导TF基因和蛋白表达的机制如何,迄今未见此类报道。我们进行了一系列临床病例采集和实验室研究,探讨Hey在CKD患者心脑血管病变发生中的地位及其具体作用机制。
目的：观察慢性肾脏病(CKD)患者血浆总同型半胱氨酸(tHcy)水平与动脉粥样硬化及心脑血管病变的关系。
方法：取健康对照35例、慢性肾脏病患者90例(维持性血液透析患者50例)作为受试者,评估受试者心脑血管病变情况,检测受试者各项生化指标及血液指标,以高效液相色谱法测定受试者血浆tHcy水平,采用彩色多普勒超声检查受试者颈动脉内-中膜层厚度(IMT)及粥样斑块的情况,评估CKD患者心脑血管病变发生情况,采取分组对照及相关分析和多元逐步Logistic回归分析评价tHcy及各项指标与CKD患者心、脑血管疾病的关系。
结果：1)CKD组中84.4%(76/90)的患者存在HHC(tHcy>15μmol/L),且CKD组血浆tHcy浓度显著高于对照组(P<0.05)；CKD患者中,73例合并心、脑血管病变者血浆tHcy浓度显著高于无心、脑血管病变者(P<0.01)。
2)CKD组颈动脉IMT,斑块阳性率显著高于对照组(P<0.05)。CKD高tHcy组(tHcy>15μmol/L)颈动脉IMT,斑块阳性率及心脑血管病变发生率显著高于CKD正常tHcy组(P<0.05)；
3)受试者血浆tHcy水平与IMT、斑块阳性率呈正相关关系(P<0.05)血浆tHcy、TG、Hb是CKD患者并发心、脑血管病的危险因素(r分别为0.351,0.712,0.199,P均<0.05)；
结论：1)CKD患者存在HHC,且合并心、脑血管病变者血浆tHcy浓度显著增高；2)CKD患者颈动脉粥样硬化及心脑血管发生率高于正常人群,且与血浆tHcy水平有关联；3)血浆tHcy水平是CKD患者动脉粥样硬化及并发心、脑血管病的危险因素。
山东大学博士学位论文第二部分目的：观察CKD患者并发急性心脑血管血栓性疾病时血浆tHcy水平及其与凝血启动因子之一——单核细胞组织因子的关系,从而进一步明确Hcy在CKD患者心脑血管并发症中的地位,探讨其可能的作用机制。
方法：根据诊断学标准取CKD患者24例作为对照组,CKD患者中AMI患者10例,ASI患者9例,以高效液相色谱法测定各组受试者tHcy,以双夹心ELISA法测定血浆中TF抗原(TFAg),以发色底物法检测单核细胞膜表面TF活性(TFact),行组间对照研究,并应用相关分析和多元逐步Logistic回归分析评价tHcy、单核细胞组织因子及各项指标与心脑血管血栓性疾病的关系。
结果：1)各组一般情况对照显示AMI组和AIS组CKD患者无论吸烟、饮酒史还是高血压、糖尿病、冠心病、脑梗发病率均高于对照组。AMI、AIS组血清肌酐及甘油三酯水平均显著高于对照组(P<0.05),但两组间无差异,AMI组血清LDL-C显著高于对照组和AIS组(P<0.05),而AIS组与对照组无差异。
2)CKD患者中AMI及ASI组血浆tHcy水平均高于对照组(P<0.05),而AMI组及AIS组间无显著差异。3)与对照组相比,AMI组与AIS组TF抗原均显著增加(P<0.05),AMI患者血浆中TF活性增高,但无统计学意义(P>0.05),AIS患者血浆中TF活性显著升高(P<0.05)。AIS组的血浆TF活性显著地高于AMI组(P<0.05)。
4)CKD患者对照组,AMI及AIS组tHcy与TFAg、TF活性均有相关关系(P<0.05),但组间差异并无统计学意义(P>0.05)。
5)CKD患者多元逐步Logistic回归分析,结果显示血浆tHcy、LDL-C是CKD患者并发急性心脑血管血栓性疾病的危险因素(回归系数分别为0.194,0.114)。
结论：在CKD患者急性心脑血管血栓性疾病中,患者tHcy和TF水平均显著增高,且二者呈正相关,提示tHcy可能与Mo TF产生增加有关,导致急性心脑血管血栓性疾病的发生。
目的：通过对不同浓度的Hcy培养下,CKD患者外周血Mo TF基因和蛋白表达的情况,核因子NF-κB抑制剂对Hcy诱导人血Mo TF的表达的影响作用,探讨Hcy对Mo TF转录、表达的作用机制,为临床上研究CKD患者并发心、脑血管病的发病机制及预防提供实验理论依据。
方法：CKD患者10例(GFR均<60ml/min),均未开始血液透析治疗抽取静脉血。分离培养单核细胞,采用不同浓度(10、50、100μmol/L、500μmol/L)Hey的RPMI1640完全培养液培养,细胞同时设阴性(PBS)对照,其中100μ-mol/LHcy组分别在0.5h、1h、2h、3h、4h检测各指标,其余各组在4h检测各指标。PDTC组在加500μmol/LHcy前先给予100mmol/LPDTC处理细胞。采用双夹心ELISA法检测产生的TFAg,一期凝固法测得PCA,并用RT-PCR方法检测Mo TFmRNA表达水平,Western blot方法检测NF-κBp65蛋白表达情况,观察不同浓度Hcy对单核细胞TFAg、PCA、NF-κBp65蛋白的影响,以及PDTC对其干预作用。
结果：1)CKD患者外周血单核细胞培养,如不加Hcy诱导,其上清液中TF含量极低,与正常人体内血浆TF含量相差无几。外周血单核细胞培养中添加不同浓度Hcy可发现上清液中TF含量明显增高,随着Hcy浓度的增加,TF在CKD患者外周血单核细胞的表达水平逐步增高,且呈剂量依赖性(P<0.05)。100μmol/LHcy作用0.5h、1h、2h、3h、4hTFAg分别为92.6±18.7、109.1±27.3、110.3±20.7、290.0±17.5、341.8±35.8pg/ml,组间差异有统计学意义(P<0.05),表明Hcy诱导TFAg的生成呈时间依赖性(P<0.05)。
2)检测各组Mo的PCA结果显示,与静息细胞比较,Hcy干预的Mo的PCA显著增加,且呈剂量依赖性(P<0.05),100μmol/L Hey作用0.5h、1h, PCA与静息细胞基本相同,而在2h、3h、4h PCA分别为17.15±1.93、31.75±2.66、37.29±3.62mU,有时间依赖性(P<0.05)。
3)结果表明随着Hcy浓度的增高,TF表达相应增加,500μmol/L Hey作用4小时达高峰(P<0.05)；结果还显示100μmol/L Hey作用0.5h、1h无表达,2h、3h、4h Mo TFmRNA逐渐升高,组间差异有统计学意义(P<0.05),表明Hcy呈浓度和时间依赖性诱导Mo组织因子mRNA表达(P<0.05)。
4)Hcy可诱导单核细胞TFmRNA表达及TFAg的生成,并具有凝血活性,其作用高峰期在4h。Hcy同时可增加单核细胞NF-κBp65蛋白表达,高峰期在1h,至第2h、4hNF-κBp65蛋白表达逐渐减弱。但如果在给予Hcy刺激前先给予100mmol/LNF-κB的抑制剂PDTC,则可见TFmRNA和TFAg、PCA及NF-κB p65的蛋白表达明显降低,与Hcy组相比,差异有显著统计学意义(P<0.05)。Hcy+PDTC组的NF-kB p65的蛋白表达甚至与对照组相似。PDTC对Hcy诱导的TFmRNA抑制作用在2h左右达高峰,随后抑制作用逐渐减弱,而对NF-κB p65的抑制作用在1h左右即达到高峰,表明Hcy对TFmRNA的诱导表达作用可被NF-κB的抑制剂PDTC给抑制,且其抑制作用晚于对NF-κB的抑制作用。
结论：Hcy诱导Mo表达TF可能是CKD患者急性血栓性心脑血管疾病的原因之一,NF-κB途径参与了Hcy诱导Mo TF表达的调节。
Homocysteinemia(Hcy) is the intermediate product of methionine.It would cause hyperhomocysteinemia(HHC) when the concentration of total Hcy(tHcy) increases pathologically.Elevated homocysteine (HCY) levels can be caused by a number of factors, including folate and B-vitamin deficiency, pre-existing atherosclerotic disease, diabetes and various drugs. Epidemiological evidence suggests that hyperhomocysteinemia (HHC) is an independent risk factor for cardiovascular and cerebrovascular disease. Chronic kidney disease (CKD) is one of the most frequent causes of HHC and when the renal insufficiency reaches the stage when dialysis treatment is initiated, more than 90% have a moderate degree of HHC (>15 lmol/l). Patients with chronic kidney disease (CKD) have high prevalence of cardiovascular disease (CVD). Study by Moustapha showed that a lμmol/l increase in tHcy was associated with a 1% higher risk of cardiovascular events. As a meta-analysis by Wald et al. showed that a 5 lmol/l increase in tHcy was associated with a 32%higher risk of cardiovascular events and a 59%higher risk of stroke, the increased Hcy levels observed in CKD patients could be considered clinically significant.But it's not the fact. So someone suggestted that HCY is a marker, rather than a cause of CVD.
It has been indicated that the expression of tissue factor (TF) in blood cells especially mononcytes plays an important role in the pathogenesis of AS and thrombosis. It was found recently that there were higher Mo TF expression in plsma of ACS patients. And it is also important in AIS patients.Many factors can induce MoTF expression. It has been reported that through the ways such as induction of the TF expression in endothelial cells (ECs), homocysteine (Hcy) could increase the ability of antithrombosis and promote thrombosis. So if can Hcy increase AMI and AIS by inducing MoTF expression? And how to induce MoTF expression? There are no reports.We carried out a series of studies to clarify this issue.
Part1
Objective To determine the relationship between hyperhomocysteinemia(HHC) and atherosclerosis and cardiovascular and cerebrovascular disease in patients with CKD.
Methods Plasma total homocysteine (tHcy) concentrations were measured by using high efficiency liquid chromatography. Carotid initial-medial thickness (IMT) the prevalence of atherosclerosis plaques were measured by echocardiography. Correlation analysis and logistic regression analysis were used to analyse the results.
Results The prevalence of HHC was 84.4% in the CKD patients. The tHcy concentration was higher in patients than those in controls (P<0.05). Cartid IMT and the prevalence of atherosclerosis plaques were positively correlated with tHcy (P<0.05). logistic regression analysis indicated that there were positively correlations a independently between cardiovascular and cerebrovascular disease in CKD patients and tHcy and other conventional risk factors such as TG、Hb.
Conclusion The results indicate that hyperhomocyseinemiamay be an independent risk factor for atherosclerosis found and cardiovascular and cerebrovascular disease in CKD patients.
Part 2
Objective This research systematicly observed blood tatal homocysteine(tHcy)level and tissue factor(TF) level produced by monocytes(Mo) in patients of CKD to determine the mechanism of Hcy in acute thrombo-cardiac-cerebro-vascular disease in patients of CKD.
Methods 10 patients with CKD who suffered AMI and 9 patients with CKD suffered ASI and 24 patients with CKD were observed. Efficiently liquid color fluorescence method measured blood tHcy level; Sandwich ELISA was performed to detect the TFAg. Chromo-substrate method was used to measure TFact on the suface of Mo,Correlation analysis and Logistic regression analysis were carried out to satistic the results.
Results The incidence rates of smoking、drinking、hypertension diabetes and CVD were higher in AMI group and AIS than that in control group (P<0.05).The levels of creatinine and TG were higher in testing group than control. The tHcy and TFAg in AMI group and AIS is obviously higher than that in control group (P<0.05).The level of TFact in AIS were higher significantly than that in AMIgroup and control group (P<0.05).There were positive relationships between tHcy and TFAg and TFact (P<0.05).tHcy and LDL-C were both independent factors of acute thrombo-cardiac-cerebro-vascular disease in patients of CKD(r=0.194,0.114).
Conclusion The levels of tHcy and TF increased in acute thrombo-cardiac-cerebro-vascular disease in patients of CKD.So tHcy may cause acute thrombo-cardiac-cerebro-vascular disease in patients of CKD by inducing the production of TF.
Part 3
Objective The Hcy-induced tissue factor (TF) expression in human monocytes(Mo) and the effect of Hey on the activity of nuclear factor-kappaB (NF-κB) were investigated to determine the action mechanism of Hey.
Methods Monocytes of ten patients of CKD were isolated and cultured, and incubated with different concentrations of Hcy/PTDC (NF-κB inhibitor).Sandwich ELISA was perfoumed to detect the TFAg.One-stage-coag method was used to measure PCA, Semi-quantitative RT-PCR was performed to detect the expression of TF mRNA in Mo.Western blot was carried out to detect the expression of NF-κB protein in nuclei.
Results There was low expression level of TF protein in the resting Mo.Hey could induce Mo expressing TF mRNA、TFAg、PCA dose-dependently after the Mo were incubated with Hey at concentrations of 10,50,100,500μmol/L (P<0.05).The concentration of TFAg were 92.6±18.7、109.1±27.3、110.3±20.7、290.0±175、341.8±35.8pg/ml after0.5h、1h、2h、3h、4h the Mo were incubated with 100μmol/L Hey (P< 0.05).Also Hey could induce TF mRNA and PCA time-dependently. Additionally, Hey could rapidly induce the activation of NF-κB and this effect could be significantly inhibited by PDTC. It was concluded that Hey could significantly induce the expression of TF in Mo and enhance the activation of NF-KB, subsequently mediate TF gene expression and protein synthesis.
Conclusion NF-KB-mediated expression of TF in Mo might be the important mechanism of atherosclerosis and thrombosis induced by Hey.
引文
[1]Lentz SR, Rodionov RN, Dayal S, Lentz, Roman N, e.t al. Hyperhomocysteinemia, endothelial dysfunction, and cardiovascular risk: the potential role of ADMA, Atheroscler Suppl.2003,4(Supple):61-65.
[2]Lubomirova M, Tzoncheva A, Petrova J, Kiperova B. Homocystein and carotid atherosclerosis in chronic renal failure, HIPPOKRATIA 2007,11, 4:205-209.
[3]Joseph J, Joseph L, Shekhawat NS,et al. Hyperhomocysteinemia leads to pathological ventricular hypertrophy in normotensive rats. Am J Physiol Heart Circ Physiol.2003,285:679-686.
[4]Chang L, Zhao J, Xu J, et al. Effects of taurine and homocysteine on calcium homeostasis and hydrogen peroxide and superoxide anions in rat myocardial mitochondria. Clin Exp Pharmacol Physiol,2004,31:237-243.
[5]Stangl V, Gunther C, Jarrin A, et al. Homocysteine inhibits TNFalpha induced endothelial adhesion molecule expression and monocyte adhesion via nuclear factor-kappaB dependent pathway. Biochem Biophys Res Commun,2009,280:1093-1100.
[6]WangH, Jiang XH, Yang F, et al.Cyclin Atranscriptional suppression is the major mechanism mediating homocysteine-induced endothelial cell growth inhibition. Blood,2002,99:939-945.
[7]Hossain GS, vanThienen JV, Wersuck GH, et al.TDAG51 is induced by homocysteine, promotes detachment mediated programmed cell death, and contributes to the development of atherosclerosis in hyperhomocyseinemia. J Biol Chem,2007,278:30317-30327.
[8]Suliman ME, Barany P, Kalantar-Zadeh K, et al.:Homocysteine in uraemia-a puzzling and conflicting story. Nephrol Dial Transplant.2005,20:16-21.
[9]Sibel Ertek, Ayse Nur Torun, Kenan Ates. The factors that affect plasma homocysteine levels, pulse wave velocity and their relationship with
cardiovascular disease indicators in peritoneal dialysis patients, Int Urol Nephrol 2010,42:211-218.
[10]Ahmed BALSAM, Mohsen M. EL KOSSI, Robert LORD, et al. Cardiovascular disease on hemodialysis:Predictors of atherosclerosis and survival, Hemodialysis International.2009,13:278-285.
[11]Westrick RJ, Bodary PF, Xu Z, et al. Deficiency of tissue factor pathway inhibitor promotes atherosclerosis and thrombosis in mice[J]. Circulation,2001,103:3044-3046.
[12]Kato H. Regulation of functions of vascular wall cells by tissue factor pathway inhibitor[J]. Arterioscler Thromb Vasc Biol,2002,22:539-548.
[13]Lindmark E, Siegbahn A.Tissue fator regulation and cytokine expression in monocyte-endothelial cell co-culturee:effects of a statin, an ACE-inhibitor and a Low-molecular-weight heparin[J]. Thromb Res,2002,108:77-84.
[14]王学锋,王鸿利主编.血栓与止血的检测及应用[M].上海：上海世界图书出版公司,2002,417-422.
[15]Mayer TE, Hamann GF, Brueclcmann HJ. Treatment of basilar artery embolism with a mechanical extraction device:necessity of flow reversal. Stroke,2008,33:2232-2236.
[16]Shiozaki T, Nakajima Y, Taneda M, et al. Efficacy of moderate hypothermia in patients with severe head injury and intracranial hypertension refractory to mild hypothermia. J Neurosurg,2003,99:47-51.
[17]Fang LIU, Ruibin HUANG, Junxia YAO, et al. Homocysteine-induced enhanced expression of tissue factor in human vascular smooth muscle cells. J Huazhong Univ Sci Technol,2008,28 (5):520-524.
[18]Christelle Foucher, Laurence Brugere, Jean-Claude Ansquer. Fenofibrate, homocysteine and renal function, Current Vascular Pharmacology,2010,8,589-603.
[19]Locatelli F, Marcelli D, Conte F. Cardiovascular disease in chronic
renal failure:The challenge continues. Nephrol Dial Transplant,2000,15:69-80.
[20]Herrmann W, Herrmann M, Obeid R.Hyperhomocysteinemia:a critical review of old and new aspects[J]. Curr Drug Metab,2007,8:17-31.
[21]Buccianti G, Baragetti I, Bamonti F, et al. Plasma homocysteine levels and cardiovascular mortality in patients with end-stage renal disease[J].J Nephrol,2004,17:405-410.
[22]McCully K S. Vascular pathology of homocysteinemia:implications for the pathogenesis of arteriosclerosis. Am J Pathol,1969,56:111-128
[23]中华医学杂志编辑委员会,北京医科大学心血管研究所.全国高同型半胱氨酸血症与疾病学术研讨会纪要.中华医学杂志,1999,79：406-410
[24]Tsai J C, Perrella M A, Yoshizumi M. Promotion of vascular smooth muscle cell growth by homocystein:a link to atherosclerosis. Proc Natl Acad Sci USA,1994,91:6369-6373
[25]Aytac Atamer, Yuksel Kocyigit, Sabahat Alisir Ecder. Effect of oxidative stress on antioxidant enzyme activities, homocysteine and lipoproteins in chronic kidney disease, JNEPHROL 2008,21:924-930.
[26]Suliman M E, Qureshi A R, Barany P, et al. Hyperhomocysteinaemia nutritional status, and cardiovascular disease in hemodialysis patients. Kidney Int,2000,57:1727-1735
[27]Touboul PJ. Common carotid artery intima-media thickness and brain infarction:the Etude du Profil Genetique de 1'Infarctus Cerebral (GENIC) case-control study. The GENIC Investigators. Circulation 2005; 102: 313-318
[28]Adaikkappan M. Evaluation of Carotid Atherosclerosis by B'Mode Ultrasonographic Study in Hypertensive Patients Compared with Normotensive Patients. Ind J Radiol Imag 2002; 12:365-368
[29]光主智.冠心病超声诊断学[M].北京：人民军医出版社,2001：131-132.
[30]Jacobsen DW. Cardiovascular disorders (risk assessment). ClinChem,
1993,65:367-373.
[31]Ziad A. Therapy of hyperhomocysteinemia in chronic kidney disease, Semin Nephrol,2006,26:24-27.
[32]PernaAF, IngrossoD, Satta E, eta.l Metabolic consequences of hyperhomocysteinemia in uremia. Am JKidneyDis,2009,38 (4Suppl1): s85-90.
[33]Guttormsen AB, Ueland PM, Faglia G, et al. Kinetic basis of hyperhomocysteinemia in patient chronic renal failure. Kidney International,1997,52:495-502.
[34]Suliman ME, Stenvinkel P, Heimburger 0, et al. Plasma sulfur amino acids in relation to cardiovascular disease, nutritional status, and diabetes mellitus in patients with chronic renal failure at start of dialysis therapy. Am J Kidney Dis.2002,40:480-488.
[35]Manns BJ, Burgges ED, Hyndman ME, et al.High dose B-vitamin treatment of atherosclerotic vascular disease in patients with endstage renal disease. AM J Kidney Dis,1999,34:669-677.
[36]刘子凡,许治强,梁伟翔,等.脑梗死患者颈动脉内膜中层厚度改变及危险因素初探.新医学,2004,35(9)：547-548.
[37]. Shoji T, Emoto M, Tabata T, et al. Advanced atherosclerosis patients with chronic renal failure. Kidney Int,2008,61:2187-2192.
[38]Sutton-TyrrellK, WolfSK, KullerLH. Blood pressure slows the progression of carotid stenosis in patientswith isolated systolic hypertension. Stroke,1994,25 (2):44.
[39].Moustapha A, Naso A, Nahlawi M, et al. Prospective study of hyperhomocysteinemia as an adverse cardiovascular risk factor in end-stage renal disease. Circulation,1998,97:138-14.
[40]Ridker PM, Canson JE, Buring JE, et al. JAMA,1999,281:1817-1821.
[41]Bostom AG, Bausserman L, Jacques PF, et al. Cystatin C as a determinant of fasting plasma total homocysteine levels in coronary artery disease
patients with normal serum creatinine[J]. Arterioscler Thromb Vasc Biol,1999,19:2241-2244.
[42]Bachmann J, Tepel M, Raidt H, et al. Hyperhomocysteinemia and the risk for vascular disease in hemodialysis patients. J Am Soci Nephrol 1995,6:121-125
[43]刘泽霖,贺石林,李家增主编.血栓性疾病的诊断与治疗.北京：人民卫生出版社,2000,18-25.
[44]Cai Q, Chen J, Ma H, et al. Association of coagulation factorⅦwith the risk of myocardial infarction in Chinese. Chin Med J,2000,113:1059-1063.
[45]Roldan V, Marin F, Fernandez, et al. Tissue factor/tissue factor pathway inhibitor system and long-term prognosis after acute myocardial infarction.Int J Cardiol,2009,78:115-119.
[46]文志斌,熊石龙,何晓凡,等.急性脑梗死发作期间组织因子途径改变的观察.中国危重病急救医学,2003,9：529-531.
[47]刘敏娟,周立红,董临江,等.血浆凝血因子Ⅶ测定在缺血性心脑血管病中的临床意义.中华血液学杂志,2000,3：152-153.
[48]Lacoviello L, Di Castelnuovo A, De Kni jff P, et al. Polymorphisms in the coagulation factorⅦgene and risk of myocardial infarction. N Engl J Med,1998,338:79-85.
[49]Sato Y, Hatakeyama K, Yamashita A, et al. Proportion of fibrin and platelets differs in thrombi on ruptured and eroded coronary atherosclerotic plaques in humans. Heart,2005,91:526-530.
[50]Seljeflot I, Hurlen M, Arnesen H.Increased levels of soluble tissue factor during long-term treatment with warfarin in patients after an acute myocardial infarction. J Thromb Haemost,2004,2:726-730.
[51]Xu G, Jin G, Fu G, et al. Polymorphisma in the coagulation factorⅦgene and risk of myocardial infarction in patients undergoing coronary angiography. Chin Med J,2007,116:1194-1197.
[52]Cote R,Wolfson C, Solymoss S, et al.Hemostatic markers in patients at
risk of cerebral ischemia.Stroke,2000,31:1856-1862.
[53]Westrick RJ, Bodary PF, Xu Z, et al. Deficiency of tissue factor pathway inhibitor promotes atherosclerosis and thrombosis in mice[J]. Circulation,2001,103:3044-3046.
[54]Ardissino D, Merlini PA, Arlens R, et al. Tissue factor in human coronary atherosclerotic plaques[J]. Clin Chim Acta,2008,219:235-240.
[55]Morel O, Toti F, Hugel B, et al. Cellular microparticles:a disseminated storage poo of bioactive vascular effectors. Curr Opin Hematol,2004,11:156-164.
[56]Meisel SR, Xu XP, Edgington TS, et al. Differentiation of adherent human monocytes into macrophages markedly enhances tissue factor protein expression and procoagulant activity. Atherosclerosis,2009,161:35-43.
[57]Becker BF, Heindl B, Kupatt C, et al. Monocyte-endothelial cell and hemostasis. Z Kardiol,2000,89:160-167.
[58]Piro O, Broge GJ Jr. Comparison of cell-surface TFPI α and β [J]. J Thromb Haemost,2005,3:2677-2683.
[59]Fryer R H, Wilson B D, Gubler D B. Homocysteine, risk factor for premature vascular disease and thrombosis, induces tissue factor activity in endothelial cells. Arterioscler Thromb,1993,13:1327-1333.
[60]中华神经学会,中华神经外科学会.脑卒中患者临床神经功能缺损程度评分标准(1995).中华神经科杂志,1996；29：379-381.
[61]夏大胜,综述.组织因子与冠心病[J].中国心血管杂志,2003,8：294-297.
[62]Jan steffel MD, Thomas F, Luscher MD, et al. Tissue factor in cardiovascular diseases molecular mechanisms and clinical implications[J]. Circulation,2006,113:722-731.
[63]Matezky S, Tani S, Kangavari S, et al. Smoking increases tissue factor expression in atherosclerotic plaques:Implications for plaques thrombogenicity[J]. Circulation,2007,102:602-604.
[64]姜德谦,黄秋霞,王俊,等.高甘油三酯冠心病患者血浆凝血因子ⅦC活性研
究[J].临床心血管病杂志,2003,19：205-206.
[65]Viswambharan H.Ming XF.Zhu S. et al. Reconstituted high-density lipoprotein inhibits thrombin-induced endothelial tissue factor expression through inhibition of RhoA and stimulation of phosphatidylinositol 3-kinase but not Akt/endothelial nitric oxide synthase.Circ Res,2004,94:918-925.
[66]Sambola A, Osende J, Hathcock J, et al. Role of risk factors in the modulation of tissue factor activity and blood thrombogenicity[J]. Circulation,2003,107:973-977.
[67]Lim HS, Blann A D, Lip Gy. Soluble CD40 ligand, soluble P-selectin, interleukin-6, and tissue factor in diabetes mellitus:relationships to cardiovascular disease and risk factor intervention. Circulation,2004, 109:2524-2528.
[68]Falk E, Fernandez-Ortiz A. Role of thrombosis in atherosclerosis and its complications. Am J Cardiol,1995,75:3-11.
[69]Moreno PR, Palacios IF, Leon MN, et al. Histopathologic comparison of human coromary in-stent and post-balloon angioplasty restenotic tissue. Am J Cardiol,1999,84:462-466.
[70]Ott I, Andrassy M, Zieglgansberger D, et al. Regulation of monocyte procoaguloant activity in acute myocardial infarction:role of tissue factor and tissue factor pathway inhibitor-1. Blood,2007,97:3721-3726.
[71]Lisowski P, Malyszko J, Lisowska A, et al. Role of the hemostatic system in pathogenesis of atherosclerosis as the main etiology of coronary ischemia[J].Pol Merkuriusz Lek,2004,16:465-467.
[72]王学锋,王鸿利主编.血栓与止血的检测及应用[M].上海：上海世界图书出版公司,2002,417-422。
[73]Mayer TE, Hamann GF, Brueclcmann HJ. Treatment of basilar artery embolism with a mechanical extraction device:necessity of flow reversal. Stroke,2002,33:2232-2236.
[74]Shiozaki T, Nakajima Y, Taneda M, et al. Efficacy of moderate hypothermia in patients with severe head injury and intracranial hypertension refractory to mild hypothermia. J Neurosurg,2003,99:47-51.
[75]Maier W,Altwegg LA, Corti R.Inflammatory markers at the site of ruptured plaque in acute myocardia infarction:locally increased interleukin-6 and serum amyloid a but decreased C-reactive protein[J]. Circulation,2005,111:1355-1361.
[76]Krupinski J, Turu MM, Font Ma, et al. Blood-borne tissue factor activity predicts major cerebrovascular events in patients undergoing carotid enderterectomy. Result from a 1-year follow-up study. Cerebrovasc Dis,2008,25:32-39.
[77]Halim A G, Hamidon B B, Cheong S k, et al. The prognostic value of tissue factor levels in acute ischaemic stroke. Singapore Med J,2006,47:400-403.
[78]den Heijer M, Willems HP, Blom HJ, et al. Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism:A randomized, placebo-controlled, doubleblind trial, Blood,2007,109:139-144.
[79]Ray JG, Kearon C, Yi Q, et al. Homocysteine-lowering therapy and risk for venous thromboembolism:a randomized trial, Ann Intern Med,2007,146: 761-767.
[80]Colucci M, Cattaneo M, Martinell I, et al.Mild hyperhomocysteinemia is associated with increased TAFI levels and reduced plasma fibrinolytic potential, Journal of Thrombosis and Haemostasis,2008,6:1571-1577.
[81]Gatt A, Makris M. Hyperhomocysteinemia and venous thrombosis,Semin Hematol,2007,44:70-76.
[82]Dure B G M, Salmon S E. Clinical staging system for multiple myeloma. Cancer,1975,36:842-842.
[83]Sambola A, Osende J, Hathcock J, et al. Role of risk factors in the modulation of tissue factor activity and blood thromboge-nicity [J].
Circulation,2003,107(7):973-977.
[84]黄细莲,钱申贤,曹利红等,外周血血细胞膜表面组织因子在脑梗塞患者的表达及活性的研究,中国实验血液学杂志,2008;16(6)：1376-1378。
[85]Manda's S K, Pendurthi U R, Rao L V.Cellular localization and trafficking of tissue factor[J]. Blood,2006,107:4746-4753
[86]Shebuski RJ, kilgore KS. Role of inflammatory mediators in thrombogenesis[J].J Pharmacol Exp Ther,2002,300:729-735
[87]Pro RT, Sato Y, Mackman N, et al.Mice deficient in tissue factor demonstrate attenuated intimal hyperplasia in response to vascular injury and decreased smooth muscle cell migration[J]. Thromb Haemost,2004,92:451-458
[88]Kann KG, Van't Veer C, Cawthern K, et al. The role of the tissue factor Pathway in initiation of coagulation [J]. Blood Coagul Fibrinolysis,1998; 9 suppl 1:S3-7
[89]Gianluca C, Marco V, Paolo F, et al. Tissue factor and cogulation factor Ⅶ levels during acute myocardial infarction:Association with genotype and adverse events[J]. Arterioscler Thromb Vasc Biol,2006,26:2800-2806
[90]Cirillo P, Cali G, Golino P, et al. Tissue factor binding of activated factorVⅦtriggers Smoth muscle cell proliferation via extracellular signal-regulated kinase activation[J]. Circulation,2004,109:2911-2916
[91]Rao VM, Pendurthi U. Tissue factor-factorⅦa signaling[J]. Arterioscler Thromb Vasc Biol,2005,25:47-56
[92]Meixia He, Zhi bin wen, Xiao fan He, et al. Observation on tissue factor pathway and some other coagulation parameters during the onset of acute cerebrocardiac thrombotic diseases[J]. Thromb Res,2002,107:223-228
[93]Bennermo M, Held C, Ericsson CG,et al. Genotype-specific increase in plasma concentrations of activated coagulation factorⅦin response to experimental inflammation. A link between infection and acute myocardial infarction[J] Thromb Haemost,2005,94:427-431
[94]刘伟,综述.组织因子途径抑制物-1与临床疾病的相关性研究[J].国外医学输血及血液学分册,2004,27：216-219.
[95]Kim HK, Song KS, Park YS,et al. Changes of plasma tissue factor and tissue factor pathway inhibitor antigen levels and induction of tissue factor expression onmonocytes in coronary artery disease[J]. Cardiology 2000,93:31-36.
[96]Hatakeyama K, Asada Y, Marutsuka K et al. Localization and activity of tissue factor in human aortic atherosclerotic lesions. Atherosclerosis, 1997,133(2):213-219.
[97]卢圣栋主编,现代分子生物学实验技术(第2版),中国协和医科大学出版社,1999.400-403.
[98]Yuichiro Sato, Yujiro Asada, Kousuke Marutsuka, et al. TFPIAoritc Smooth MUscle cell Migration Induced by TF/FVIIa complex Thromb Haemost,1997;78:1138.
[99]田军,张金元,胡大勇.肾功能损害对血浆同型半胱氨酸浓度的影响[J].中国血液净化,2005,10：542-544.
[100]Van de stolpe A, Van de saag PT. Intercellular adhesion molecules-1, J Mol Med,1996; 74 (1):13.
[101]Suliman ME, Stenvinkel P, Heimburger O, et al. Plasma sulfur amino acids in relation to cardiovascular disease, nutritional status, and diabetes mellitus in patients with chronic renal failure at start of dialysis therapy[J]. Am J Kidney Dis.2002,40:480-488.
[102]Hofman M A, Lalla E, Lu Y et al. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest,2009,107:675-683.
[103]Bozkurt A, Toyaksi H, Acarturk E et al. The effects of hyperhomocyteinemia on the presence, extent, and severity of coronary artery disease. Jpn Heart J,2003,44(3):357-368.
[104]Soysal D, Savas S, Susam I et al. The association of plasma
homocysteine, coronary risk factors and serum nitrite in patients with coronary artery disease, vascular syndrome x and healthy subjects. Anadolu Kardiyol Derg,2003,3(1):26-34.
[105]Faria-Neto J R, Chagas A C, Bydlowski S P et al. Hyperhomocystinemia in patients with coronary artery disease. Braz J Med Biol Res, 2006,39 (4):455-463.
[106]Fanapour P C, Yug B, Kochar M S. Hyperhomocysteinemia:an additional cardiovascular risk factor. WMJ,1999,98(8):51-54.
[107]王鸿利主编。血液学和血液学检验(第二版),北京：人民卫生出版社,1997：280.
[108]Adama M J, Thom J, Hankey G J, et al. The tissue factor pathway in ischemic stroke[J]. Blood Coagulation and Fibrinolysis,2006,17:527-532
[109]Kann KG, Van't Veer C, Cawthern K, et al. The role of the tissue factor Pathway in initiation of coagulation [J]. Blood Coagul Fibrinolysis,1998; 9 suppl 1:S3-7.
[110]Savelieva I, BaiPai A, Camm AJ. Stroke in atrial fibrillation:update on Pathophysiology, new antithrombotic therapies, and evolution of Procedures and devices[J]. Ann Med,2007,39:371-391
[111]Yuichiro Sato, Yujiro Asada, Kousuke Marutsuka, et al,TFPI Aoritc Smooth MUscle cell Migration Induced by TF/FVIIa complex, Thromb Haemost,1997,78:1138.
[112]PernaAF, IngrossoD, Satta E, eta.l Metabolic consequences of hyperhomocysteinemia in uremia. Am JKidneyDis,2001,38 (4Suppl1):s85-90
[113]Ikeda U, Ikeda M, Minota S, et al. Homocysteine Increases Nitric Oxide Synthesis in Cytokine-Stimulated Vascular Smooth Muscle Cells[J]. Circulation,1999,99(9):1230.
[114]Ortego M, Bustos C, Hernandez-Presa M A et al. Atorvastatin reduces NF-κB activation and chemokine expression in vascular smooth muscle cells and mononuclear cells. Atherosclerosis,1999,147:253-261.
[115]Wilson S H, Caplice N M, Simari R D et al. Activated nuclear factor-κB is present in the coronary vasculature in experimental hypercholesterolemia. Atherosclerosis,2000,148:23-30.
[116]Yan Z Q, Sirsjo A, Bochaton-Piallat M L et al. Augmented expression of inducible NO synthase in vascular smooth muscle cells during aging is associated with enhanced NF-kappaB activation. Arterioscler Thromb Vasc Biol,1999,19(12):2854-2862.
[117]Brand K, Page S, Rogler G et al. Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion. J Clin Invest,1996,97:1715-1722.
[118]Katsuyama K, Shichiri M, Marumo F et al. Role of nuclear factor-kappaB activation in cytokine-and sphingomyelinase-stimulated inducible nitric oxide synthase gene expression in vascular smooth muscle cells. Endocrinology,1998,139(11):4506-4512.
[119]Welch G N, Upchurch G R Jr, Farivar R S et al. Homocysteine-induced nitric oxide production in vascular smooth muscle cells by NF-κ B-dependent transcriptional activation of Nos2. Proc Assoc Am Physicians,1998,110:22-31.
[120]Ikeda U, Ikeda M, Minota S et al. Homocysteine increases nitric oxide synthesis in cytokine-stimulated vascular smooth muscle cells. Circulation,1999,99 (9):1230-1235.
[121]Lentz SR, Rodionov RN, Dayal S, Lentz, Roman N, et al. Hyperhomocysteinemia, endothelial dysfunction, and cardiovascular risk: the potential role of ADMA, Atheroscler Suppl.2003,4(Supple):61-65.
[122]Austin RC, Lentz SR, Werstuck GH. Role of hyperhoocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell Death and Differentiation,2004,11:56-64.
[123]Joseph J, Joseph L, Shekhawat NS, et al. Hyperhomocysteinemia leads to pathological ventricular hypertrophy in normotensive rats. Am J Physiol
Heart Circ Physiol.2003,285:679-686.
[124]Chang L, Zhao J, Xu J, et al. Effects of taurine and homocysteine on calcium homeostasis and hydrogen peroxide and superoxide anions in rat myocardial mitochondria. Clin Exp Pharmacol Physiol,2004,31:237-243.
[125]Stangl V, Gunther C, Jarrin A, et al. Homocysteine inhibits TNFalpha induced endothelial adhesion molecule expression and monocyte adhesion via nuclear factor-kappaB dependent pathway. Biochem Biophys Res Commun,2009,280:1093-1100.
[126]WangH, Jiang XH, Yang F, et al. Cyclin Atranscriptional suppression is the major mechanism mediating homocysteine-induced endothelial cell growth inhibition. Blood,2002,99:939-945.
[127]Hossain GS, vanThienen JV, Wersuck GH, et al. TDAG51 is induced by homocysteine, promotes detachment mediated programmed cell death, and contributes to the development of atherosclerosis in hyperhomocyseinemia. J Biol Chem,2003,278:30317-30327.
[128]Suliman ME, Barany P, Kalantar-Zadeh K, et al.:Homocysteine in uraemia-a puzzling and conflicting story. Nephrol Dial Transplant.2005,20:16-21.
[129]Moustapha A, Naso A, Nahlawi M, et al. Prospective study of hyperhomocysteinemia as an adverse cardiovascular risk factor in end-stage renal disease[J]. Circulation,1998,97:138-141.
[130]Toyoda K, Fujii K, Ando T, et al. Incidence, etiology, and outcome of stroke in patients on continuous ambulatory peritoneal dialysis. Cerebrovaseases,2004,17(2-3):98-105.
[131]Seliger SL, Gillen DL, Longstreth WT, et al. Elevated risk of stroke among patients with end-stage renal disease. Kidney Int,2003,64 (2):603-609.
[132]Guttormsen AB, Ueland PM, Faglia G, et al. Kinetic basis of hyperhomocysteinemia in patient chronic renal failure [J]. Kidney
International,1997,52:495-502.
[133]Dayal S, Arning E, Bottiglieri T, et al. Cerebral vascular dysfunction mediated by superoxide in hyperhomocysteinemic mice. Stroke, 2004,35(8):1957-1962.
[134]Dayal S, Brown KL, Weydert CJ, et al. Deficiency of glutathione peroxidase-1 sensitizes hyperhomocysteinemic mice to endothelial dysfunction. ArteriosclerThromb Vasc Biol,2002,22(12):1996-2002
[135]Kikawa R:Chronie complieations in diabetes mellitus, Br J Nutr.2000.84 (12):183-185.
[136]SuematsuN, Ojaimi C, Kinugawa S, et al. Hyperhomocysteinemia alters cardiac substrate metabolism by impairing nitric oxide bioavailability through oxidative stress. Circulation,2007,115(2):255-262.
[137]Dickinson CJ. Stroke and their relationship to hypertension. Curr Opin Nephrol Hypertens.2003,12:91-99.
[138]Handy DE, Zhang Y, Loscalzo J. Homocysteine down-regulates cellular glutathione peroxidase (GPxl) by decreasing translation. J Biol Chem,2005, 280(16):15518-15525.
[139]Ridker PM, Rifai N, Rose L, et al. Comparision of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med,1997,336:973-979.
[140]Barbato JC, Catanescu 0, Murray K, et al. Targeting of metallothionein by L-homocysteine:a novel mechanism for disruption of zinc and redoxhomeostasis. ArteriosclerThromb Vasc Biol,2007, 27(1):49-54.
[141]戚本玲,张银环,郭和平,等.高Hcy血症与冠心病.临床心血管病杂志,2001,17(8)：359.
[142]Mujumdar VS, Aru GM, Tyagi SC. Induction of oxidative stress by homocyst(e) ine impairs endothelial function. JCell Biochem,2001, 82(3):491-500.
[143]Loveras J. Roquer J. Puig JM.et al. Stroke in renal transplant rccipients:epidemiology predietive risk factors and outeome.Clin Transplant.2003,17(1):1-8.
[144]中华医学会肾脏病分会透析移植登记工作组,1999年度全国透析移植登记报告,中华肾脏病杂志,2001：17：77-78.
[145]Tozawo M, Iseki K,Iseki C,et al. Pulse pressure and risk of total mortality and cardiovascular events in patients on chronic hemodialysis. Kidney Int,2002,61:717-726.
[146]Suhara T, Fukuo K, Yasuda O, et al. Homocysteine enhances endothelial apoptosis via upregulation of Fas-mediated pathways. Hypertension,2004, 43(6):1208-1213.
[147]Zhang C, Cai Y, Adachi MT, et al. Homocysteine induces programmed cell death in human vascular endothelial cells through activation of the unfolded protein response. J Biol Chem,2001,276(38):35867-35874.
[148]Lentz SR, Mechanisms of homocysteine-induced atherothrombosis. J ThrombHaemost,2005,3 (8):1646-1654.
[149]Werstuck GH, Lentz SR, Dayal S, et al. Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. J Clin Invest,2001,107(10):1263-1273.
[150]Winbeck K, Poppert H,Etgen T,et al.Prognostic relevance of early serial C-reactive protein measurements after first ischemic stroke. Stroke,2002,33(10):2459-2464.
[151]Himmelfarb J, Stenvinkel P, Ikizler TA, et al. The elephant in uremia: Oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney Int,2002,62:1524-1538.
[152]Martinet W, Knaapen MW, De Meyer GR, et al. Elevated levels of oxidative DNA damage and DNA repair enzymes in human atheposclerotic plaques, Crculation,2002,106:927-932.
[153]Ferguson E, Hogg N, Antholine WE, et al. Characterization of the adduct formed from the reaction between homocysteine thiolactone and low-density lipoprotein:antioxidant implications. Free Radic Biol Med, 1999,26(7-8):968-977.
[154]Vignini A, Nanetti L, Bacchetti T, et al. Modification induced by homocysteine and low-density lipoprotein on human aortic endothelial cells:an in vitro study.J Clin Endocrinol Metab,2004,89(9):4558-4561
[155]Pitoulias GA, Tachtsi MD, TsiaousisPZ,et al. Hyperhomocysteinemia and hypercoagulable state in carotid plaque evolution. Novel risk factors or coincidental risk predictors? Int Angiol,2007,26(3):270-278.
[156]Masakazu Ogawaa, Satoshi Abea, Masigoa, et al. Homocysteine and hemostatic disorder as a risk factor for myocardial infarction at a young age.Thrombosis Research,2003,109:253-258.
[157]Khajuria A, Houston DS, Induction of monocyte tissue factor expression by homocysteine:a possible mechanism for thrombosis. Blood, 2000,96:966-972.
[158]Durand P, Lussier-Cacan S, Blache D. Acute methionnine load induced hyperhomocysteinemia enhanceplatelet-aggregation, thromboxane load induced hyperhomocysteinemia enhances platelet-aggregation, thromboxane biosynthesis, and macrophage-derived tissue factor activity in rats. Faseb J,1997,11:1157-1168.
[159]Hofmann MA, Lalla E, Lu Y, et al. Hypehomocysteinemia enhances vascular inflammation and accelerates atherosis in a murine model. J Clin Invest.2001,107(6):675-683.
[160]Gotlieb AI. Smooth muscle and endothelial cell function in the pathogenesis of atherosclerosis. Can MedAssoc J,1982,126(8):903-908.
[161]Tofler GH, D Agostino RB, JACQUES pe, ET AL. Associatine and arterial diseased homocystine levels and impaired fibrinolytic potential mechanism for cardiovascular risk. Thromb Haemost.2002,88(5):799-804.
[162]Sauls DL, Lockhart E, Warren ME,et al. Modification of fibrinogen by homocysteine thiolactone increases resistance to fibrinolysis:a potential mechanism of the thrombotic tendency in hyperhomocysteinemia. Biochemistry,2006,45(8):2480-2487.
[163]Hajjar KA, Mauri L, Jacovina AT, et al. Tissue plasminogen activator bindingto the annexinⅡtail domain. Directmodulation by homocysteine.J Biol Chem,1998,273(16):9987-9993.
[164]Ling Q, Hajjar KA. Inhibition of endothelial cell thromboresistance by homocysteine. JNutr,2000,130 (2S Suppl):373-376.
[165]Midorikawa S, Sanada H, Hashimoto S, et al. Enhancement by homocysteine of plasminogen activator inhibitor-1 gene expression and secretion from vascular endothelial and smooth mscle cells. Biochem Biophys Res Commun.2000,272(1):182-185.
[166]Kernan WN, Viscoli CM, Inzucchi SE, et al. Insulin resistance among patients with ischemic stroke and TIA. Stroke,2002,33:389.
[167]Leoncini G, Pascale R, Signorello MG. et al. Effects of homocysteine on 1-arginine transport and nitric oxide formation in human platelets. Eur J Clin Invest.2003,33(8):713-719.
[168]Bostom AG, Shrmin D, Lapane KL,et al.Hyper homocysteinemia and traditional cardiocascular diseae risk factors in end-stage renal diseade patients on dialysis case-contorl study. Atterrosclerosis.1995,114:93.
[169]Signorello MG, Pascale R, Leoncini G. Effect of homocysteine on arachidonic aid release in human platets. Eur J Clin Invest.2002,32 (4):279-284.
[170]Wang G,0 K. Homocysteine stimulates the expression of monocyte chemoattractant protein-1 (CCR2) in human monocytes:possible involvement of oxygen free radicals. Biochem. J.2001,357:233-240.
[171]Poddar R, Sivasubramanian N, Dibello PM,et al. Homocysteine induces expression an secretion of monocte chemoattractant protein-q and
interleukin-8 in human aortic endothelial cells:implications for vascular disease. Circulation.2001,103:2717-2723.
[172]Wang G, Siow YL and 0 K. Homocysteine induces monocyte chemoattractant protein-1 expression b activating NF-kappa B in THP-1 macrophages. Am. J. Phtsiol. Heart Circ. Physiol.2001,280:2840-2847.
[173]Welch GN, Upchurch GR, Keancy JF, et al. Homocysteine decreases cell redox potential in vascular amooth muscle cells. J Am Coll Cardiol.1996,27:164.
[174]黄瑞滨,洪梅,仲任等,同型半胱氨酸对人单核细胞组织因子表达的影响,Journal of Clinical Hematology,2004,17(3),130-134.
[175]Hofman M A, Lalla E, Lu Y et al. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest,2001,107:675-683
[176]Bozkurt A, Toyaksi H, Acarturk E et al. The effects of hyperhomocyteinemia on the presence, extent, and severity of coronary artery disease. Jpn Heart J,2003,44(3):357-368
[177]Soysal D, Savas S, Susam I et al. The association of plasma homocysteine, coronary risk factors and serum nitrite in patients with coronary artery disease, vascular syndrome x and healthy subjects. Anadolu Kardiyol Derg,2003,3(1):26-34
[178]Faria-Neto J R, Chagas A C, Bydlowski S P et al. Hyperhomocystinemia in patients with coronary artery disease. Braz J Med Biol Res, 2006,39 (4):455-463
[179]Fanapour P C, Yug B, Kochar M S. Hyperhomocysteinemia:an additional cardiovascular risk factor. WMJ,1999,98(8):51-54
[180]Pollman M J, Yamada T, Horiuchi M et al. Vasoactive substances regulate vascular smooth muscle cell apoptosis. Countervailing influences of nitric oxide and angiotensin. Cir Res,1996,79:748-756
[181]王宁菊,陈耀平,杨宝护。同型半眯氨酸对乳腺癌患者外周血单核细胞组
织因子表达的影响,宁夏医学院学报,2008,10(30)：570-572
[182]Oeth P, Parry GC; Mackman N, et al. Regulation of the tissue factor gene in human monocytic cells. Role of AP-1, NF-kappa B/Rel, and Spl proteins in uninduced and lipopolysaccharide-induced expression. Arterioscler Thromb Vasc Biol,1997,17:365-374.
[183]Mackman N. Lipopolysaccharide induction of gene expression in human monocytic cells[J]. Immunol Res,2000,21:247-251.
[184]黄瑞滨,洪梅,仲任等,同型半胱氨酸对人单核细胞组织因子表达的影响,Journal of Clinical Hematology,2004,17(3),130-134.
[185]Mackman N. Regulation of tissue factor gene expression in human monocytic and endothelial cells[J]. Haemostasis,1996,26(1):17-19.
[186]Oeth PA, Parry GC, Kunsch C, et al. Lipopolysaccharide induction oftissue factor gene expression in monocytic cells ismediated by binding of c-Rel/p65 heterodimers to a kappa B-like site[J]. Mol Cell Biol,1994,14:3772-3781.
[187]Groupp ER, Donovan-Peluso M. Lipopolysaccharide induction of THP-1 cells activates binding of c-Jun, Ets, and Egr-1 to the tissue factor promoter[J]. J Biol Chem,1996,271:12423-12430.
[188]Lindmark E, Tenno T, Siegbahn A, et al. Role of platelet P-selectin and CD40 ligand in the induction of monocytic tissue factor expression. Arterioscler Thromb Vasc Biol,2000,20:2322-2328.
[189]Nakagomi A, Freedman SB, Geczy CL, et al. Interferon-gamma and lipopolysaccharide potentiate monocyte tissue factor induction by C-reactive protein:relationship with age, sex, and hormone replacement treatment. Circulation,2000,101:1785-1791.
[190]Amirkhosravi A, Alexander M, May K, et al. The importance of platelets in the expression ofmonocyte tissue factor antigenmeasured by a newwhole blood flow cytometric assay. Thromb Haemost,1996,75:87.
[191]Pouplard C, Iochmann S, Renard B, et al. Induction ofmonocyte tissue
factor expression by antibodies to heparin-platelet factor 4 complexes developed in heparin-induced thrombocytopenia. Blood,2001,97:3300.
[192]Becker BF, Heindl B, Kupatt C, et al. Endothelial function and hemostasis. Z Kardiol,2000,89:160-167.
[193]IkedaU, Takahashi M, Shimada K, et al.Monocyte-endothelial cell interaction in atherogenesis and thrombosis. Clin Cardiol,1998,21:11.
[194]Baron AD. Vascular reactivity. Am J Cardiol,1999,84:25-27.
[195]Napoleone E, Di Santo A, Lorenzet R, et al. Monocytes upregulate endothelial cell expression of tissue factor:a role for cell-cell contact and cross-talk[J]. Blood,1997,89:541-549.
[196]Marx N, Neumann FJ, Zohlnhofer D, et al. Enhancement of monocyte procoagulant activity by adhesion on vascular smoothmuscle cells and intercellular adhesion molecule-1-transfected Chinese hamster ovary cells. Circulation,1998,98:906-911.
[197]Bucher HC, Griffith LE, Guyatt GH, et al. Systematic review on the risk and benefit of different cholesterol-lowering interventions. Arterioscler Thromb Vasc Biol,1999,19:187-95.
[198]Tun A, Khan IA. Myocardial infarction with normal coronary arteries:the pathologic and clinical perspectives [J]. Angiology,2001,52: 299.
[199]Cirillo P, Cali G, Golino P, et al. Tissue factor binding of activated factorⅦtrigger Smoth muscle cell proliferation via extracellular signal-regulated kinas activation. Circulation,2004,109:2911-2916
[200]Rao VM, Pendurthi U. Tissue factor-factorⅦa signaling. Arterioscler ThrombVasc Biol,2005,25:47-56
[201]Abe Y,Kondo M, Kubota T, et al. Noninvasive assessment of coronar microvascular dysfuntion using TC-99m tetrofosmin SPECT in patients with acut myocardial infarction[J]. J-Nucl-Cardiol,2004,11:562-569
[202]Osterud B. A global view on the role of monocytes and platelets in
atherogenesis. Thromb Res,1997,85:1-22.
[203]Meixia He, Zhi bin wen, Xiao fan He, et al. Observation on tissue factor pathway and some other coagulation parameters during the onset of acute cerebrocardia thrombotic diseases[J]. Thromb Res,2002,107:223-228
[204]Lusis AJ. Atherosclerosis [J]. Nature,2000,407:233-41.
[205]MorenoPR, Palacios IF, LeonMN,et al. Histopathologic comparison of human coronary in-stent and post-balloon angioplasty restenotic tissue. Am J Cardiol,1999,84:462-466.
[206]Ott I, Andrassy M, Zieglgansberger D, Geith S, et al. Regulation of monocyte procoagulant activity in acute myocardial infarction:role of tissue factor and tissue factor pathway inhibitor-1. Blood,2001,97:3721.
[207]Freeburn JC, Wallace JM, Strain JJ, et al. Monocyte tissue factor-like activity in post myocardial infarction patients. Br J Haematol,1998,102:605-608.
[1] Touboul PJ. Common carotid artery intima-media thickness and brain infarction:the Etude du Profil Genetique de l'Infarctus Cerebral (GENIC) case-control study. The GENIC Investigators.Circulation 2000; 102:313-318
[2]Adaikkappan M. Evaluation of Carotid Atherosclerosis by B'Mode Ultrasonographic Study in Hypertensive Patients Compared with Normotensive Patients. Ind J Radiol Imag 2002; 12: 365-368
[3] Chambless LE. Risk factors for progression of common carotid atherosclerosis:the Atherosclerosis Risk in Communities Study, 1987-1998. Am J Epidemiol 2002;155:38-47
[4] Francis ME. Association between serum homocysteine and markers of impaired kidney function in adults in the United States. Kidney Int 2004; 66: 303-312
[5] Frantzen F. Enzyme conversion immunoassay for determining total homocysteine in plasma or serum. Clin Chem 1998,44:311-316
[6] Stehouwer CD. Serum homocysteine and risk of coronary heart disease and cerebrovascular disease in elderly men: a 10-year follow-up. Arterioscler Thromb VascBiol 1998; 18:1895-1901
[7] Zanchetti A. The Verapamil in Hypertension and Atherosclerosis Study (VHAS): results of long-term randomized treatment with either verapamil or chlorthalidone on carotid intima-media thickness. J Hypertens 1998; 16:1667-1676
[8] Zanchetti A. Risk factors associated with alterations in carotid intima-media thickness in hypertension: baseline data from the European Lacidipine Study on Atherosclerosis. J Hypertens 1998; 16: 949-961
[9] Ando F. Ultrasonic evaluation of common carotid intima-media thickness (IMT) -influence of local plaque on the relationship between IMT and age. J Epidemiol 2000; 10(Suppl.l):S10-S17
[10] Kissinger G, Hoppichler F. Prevalence of increasing carotid artery atherosclerosis in chronic renal failure: an ultrasonographic study. Hypertonie 2003;
[11] Bots ML. Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation 1997; 96:1432-1437
[12] Konings C. Arterial wall properties in patients with renal failure. Am J Kidney Dis 2002; 39:1206-1212
[13] Shoji T. Advanced atherosclerosis in predialysis patients with chronic renal failure. Kidney Int 2002; 61:2187-2192
[14] Leoncini G. Mild renal dysfunction and subclinical cardiovascular damage in primary hypertension. Hypertension 2003; 42:14-18
[15] Leskinen Y. Homocysteine and carotid atherosclerosis in chronic renal failure-the confounding effect of renal function. Atherosclerosis 2004; 175: 315-323
[16] Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000; 355: 253-259
[17] Bostom AG, Culleton BF. Hyperhomocysteinemia in chronic renal disease. J Am Soc Nephrol 1999; 10: 891-900 18. Rahn KH. Vessel wall alterations in patients with renal failure.Hypertens Res 2000; 23: 3-6
[18] Rahn KH. Vessel wall alterations in patients with renal failure. Hypertens Res 2000;23:3-6
[1]JArkel YS.Alteration in second phase platelet aggregation associated with an emotionally stress fulactivity. Thrombosis and Haemostasis 2007,38: 552-561.
[2]Bostom AG.High dose B vitamin treatment of hyperhomocysteinemia in dialysis patients. Kidney Int,2001,49:147-152.
[3]Brulez HFH.The impact of an amino acid-based peritoneal dialysis fluide on plasma total homocysteine levels, lipid profile and body fat mass.Nephrol Dial Trans plant,1998,14:154-159.
[4]DeGroot PG. Endothelial cell dysfunction in homocystinuria. Eur J Clin In vest,1998,13: 405-410.
[5]Heijer M.Hyperhomocysteinemia and venous thrombosis: A meta-analysis. Thromb Haemos,2002,80: 874-877.
[6]Durand P. Pro-thrombotic effects of a folic acid deficient diet in rat platelets and macrophage related to ele ated homocysteine and decreased n-3 poly unsaturated fatty acids. Atherosclerosis51998,121: 231-243.
[7]Fryer RH.Homocysteine, a risk factor for premature vascular disease and thrombosis, induces tissue factor activity in endothelial cells. Arterioscler Thromb,2000,13:1327-1333.
[8]Gra ham IM. Plasma homocysteine as a risk factor for vascular disease: The European Concerted Action Project. JAMA, 1997,2 77:1775-1781.
[9]Heinecke J. The role of sulfur-containing amino acids in superoxide production and modification of low-density lipoprotein by arterial smooth muscle cells. J Biol Chem,2002,262:10098-10103.
[10]Khajuria A and Hous ton DS.Induction of monocyte tissue factor expression by homocysteine: a possible mechanism for thrombosis. Blood, 2000,96: 966-972.[1 l]Kim SS. Hyperhomocysteinemia as a possible role for atherosclerosis in CAPD patients. Adv Perit Dial,1994,10: 282-285.
[12]Lu ther T, Flow cytometric analysis of tissue factor (TF) expression on stimulated monocytes- comparison to procoagulant activity of mononuclear blood cells.Blut,1999, 61: 375-378.
[13]Mezzano D,Hemostatic disorder of uremia: the platelet defect, main determinant of the prolonged bleeding time, is correlated with in dices of activation of coagulation and fibrinolysis. Thromb Haemost,2005,76: 312-321.
[14]Moal V.Impaired expression of glycoproteinson resting and stimulated platelets in uraemic patients.Nephrol Dial Transplant,2006,18:1834-1841