磷酸吡哆醛丁咯地尔对大鼠高同型半胱氨酸血症生物学效应的影响
|
摘要
目的
观察磷酸吡哆醛丁咯地尔(buflomedil pyridoxal phosphate, BPP)对大鼠高同型半肤氨酸血症生物学效应的影响,探讨磷酸吡哆醛丁咯地尔能否拮抗高同型半肤氨酸血症的生物学效应及其作用机制。
方法
健康雄性SD大鼠40只,随机分为5组,每组8只：1组为BPP组,给予2%蛋氨酸饲料(20g蛋氨酸/1kg正常饲料)+BPP灌胃；2组为丁咯地尔+维生素B6组,给予2%蛋氨酸饲料+丁咯地尔、维生素B6灌胃；3组为丁咯地尔组,给予2%蛋氨酸饲料+丁咯地尔灌胃；4组为蛋氨酸模型组,给予2%蛋氨酸饲料+生理盐水灌胃；5组为正常对照组,给予正常饲料+生理盐水灌胃。药物灌胃剂量根据等效剂量系数折算法换算,每只大鼠每天灌胃两次,连续喂养8周。第8周末,用10%水合氯醛注射液麻醉大鼠,腹主动脉取血离心制备血浆,放入-20℃冻存,用ELISA检测同型半胱氨酸(homocysteine,Hcy)、超氧化物歧化酶(superoxide dismutase, SOD)的含量。摘取一侧颈动脉,用western blot检测劲动脉内皮型一氧化氮合成酶(endothelial nitric oxide synthase, eNOS)的蛋白表达。
结果
1.蛋氨酸模型组大鼠血浆Hcy浓度比正常对照组升高(P<0.01),BPP、丁咯地尔+维生素B6、丁咯地尔组血浆Hcy浓度均比蛋氨酸模型组低(P<0.05),BPP组血浆Hcy浓度低于丁咯地尔+维生素B6组、丁咯地尔组(P<0.01),接近正常对照组(P>0.05)
2.蛋氨酸模型组大鼠血浆SOD浓度比正常对照组降低(P<0.01),BPP、丁咯地尔+维生素B6、丁咯地尔组血浆SOD浓度均比蛋氨酸模型组高(P<0.05),BPP组血浆SOD浓度高于丁咯地尔组(P<0.01),但与丁咯地尔+维生素B6组无明显差别(P>0.05),均低于正常对照组(P<0.05)。
3.蛋氨酸模型组大鼠颈动脉eNOS蛋白表达比正常对照组降低(P<0.01),BPP、丁咯地尔+维生素B6、丁咯地尔组eNOS蛋白表达均比蛋氨酸模型组高(P<0.05),BPP组eONS蛋白表达高于丁咯地尔+维生素B6组、丁咯地尔组(P<0.01),接近正常对照组(P>0.05)
4.所有大鼠颈动脉eONS蛋白表达与血浆Hcy浓度负相关,相关系数为-0.9,P<0.05。
结论
1.磷酸吡哆醛丁咯地尔、丁咯地尔+维生素B6、丁咯地尔均可以降低蛋氨酸负荷所致的高Hcy血症,并可能通过抑制Hcy诱导的SOD、eNOS表达下调来拮抗高Hcy血症的生物学效应。
2.高浓度同型半胱氨酸可以通过抑制eNOS表达,减少NO生成。
3.磷酸吡哆醛丁咯地尔拮抗高Hcy血症生物学效应的作用显著,优于丁咯地尔+维生素B6,可能成为防治高Hcy血症的新思路。
Objective
To evaluate the effect of buflomedil pyridoxal phosphate on hyperhomocysteinemia(HHcy).
Methods
40male Sprague-Dawley rats were randomly divided into five groups:buflomedil pyridoxal phosphate (BPP) group; buflomedil+VitB6group; buflomedil group; Met group; the controlled group. At the end of the8th weeks, get blood plasma and unilateral carotid artery to measure the concentration of homocysteine and superoxide dismutase, the protein expression of endothelial nitric oxide synthase.
Results
1.The Hcy concentration of Met group was significantly higher than controlled group(P<0.01), the Hcy concentration of the BPP, buflomedil+vitamin B6, buflomedil group was lower than Met group(P<0.01), the Hcy concentration of BPP group was significantly lower than buflomedil+vitamin B6group(P<0.01), close to the controlled group(P>0.05).
2.The SOD concentration of Met group was significantly lower than controlled group(P<0.01), the SOD concentration of the BPP, buflomedil+vitamin B6, buflomedil group was higher than Met group(P <0.05); the SOD concentration of BPP group was close to buflomedil+vitamin B6group.
3. The eNOS expression of Met group was significantly lower than controlled group(P<0.01), the eNOS expression of the BPP, buflomedil+vitamin B6, buflomedil group was higher than Met group(P<0.01), the eNOS expression of BPP group was significantly higher than buflomedil+vitamin B6group(P<0.01), close to the controlled group(P>0.05).
4. The eNOS expression was negatively correlated with Hcy concentration.
Conclusions
1. Buflomedil pyridoxal phosphate, buflomedil+vitamin B6, buflomedil can all decrease plasma Hcy level, and may prevent the negative effect of Hcy to SOD, eNOS.
2. Homocysteine can reduce NO production through suppressing the expression of eNOS.
3. The influence of buflomedil pyridoxal phosphate on the biological effect of hyperhomocysteinemia was significant, and better than buflomedil+vitamin B6.
观察磷酸吡哆醛丁咯地尔(buflomedil pyridoxal phosphate, BPP)对大鼠高同型半肤氨酸血症生物学效应的影响,探讨磷酸吡哆醛丁咯地尔能否拮抗高同型半肤氨酸血症的生物学效应及其作用机制。
方法
健康雄性SD大鼠40只,随机分为5组,每组8只：1组为BPP组,给予2%蛋氨酸饲料(20g蛋氨酸/1kg正常饲料)+BPP灌胃；2组为丁咯地尔+维生素B6组,给予2%蛋氨酸饲料+丁咯地尔、维生素B6灌胃；3组为丁咯地尔组,给予2%蛋氨酸饲料+丁咯地尔灌胃；4组为蛋氨酸模型组,给予2%蛋氨酸饲料+生理盐水灌胃；5组为正常对照组,给予正常饲料+生理盐水灌胃。药物灌胃剂量根据等效剂量系数折算法换算,每只大鼠每天灌胃两次,连续喂养8周。第8周末,用10%水合氯醛注射液麻醉大鼠,腹主动脉取血离心制备血浆,放入-20℃冻存,用ELISA检测同型半胱氨酸(homocysteine,Hcy)、超氧化物歧化酶(superoxide dismutase, SOD)的含量。摘取一侧颈动脉,用western blot检测劲动脉内皮型一氧化氮合成酶(endothelial nitric oxide synthase, eNOS)的蛋白表达。
结果
1.蛋氨酸模型组大鼠血浆Hcy浓度比正常对照组升高(P<0.01),BPP、丁咯地尔+维生素B6、丁咯地尔组血浆Hcy浓度均比蛋氨酸模型组低(P<0.05),BPP组血浆Hcy浓度低于丁咯地尔+维生素B6组、丁咯地尔组(P<0.01),接近正常对照组(P>0.05)
2.蛋氨酸模型组大鼠血浆SOD浓度比正常对照组降低(P<0.01),BPP、丁咯地尔+维生素B6、丁咯地尔组血浆SOD浓度均比蛋氨酸模型组高(P<0.05),BPP组血浆SOD浓度高于丁咯地尔组(P<0.01),但与丁咯地尔+维生素B6组无明显差别(P>0.05),均低于正常对照组(P<0.05)。
3.蛋氨酸模型组大鼠颈动脉eNOS蛋白表达比正常对照组降低(P<0.01),BPP、丁咯地尔+维生素B6、丁咯地尔组eNOS蛋白表达均比蛋氨酸模型组高(P<0.05),BPP组eONS蛋白表达高于丁咯地尔+维生素B6组、丁咯地尔组(P<0.01),接近正常对照组(P>0.05)
4.所有大鼠颈动脉eONS蛋白表达与血浆Hcy浓度负相关,相关系数为-0.9,P<0.05。
结论
1.磷酸吡哆醛丁咯地尔、丁咯地尔+维生素B6、丁咯地尔均可以降低蛋氨酸负荷所致的高Hcy血症,并可能通过抑制Hcy诱导的SOD、eNOS表达下调来拮抗高Hcy血症的生物学效应。
2.高浓度同型半胱氨酸可以通过抑制eNOS表达,减少NO生成。
3.磷酸吡哆醛丁咯地尔拮抗高Hcy血症生物学效应的作用显著,优于丁咯地尔+维生素B6,可能成为防治高Hcy血症的新思路。
Objective
To evaluate the effect of buflomedil pyridoxal phosphate on hyperhomocysteinemia(HHcy).
Methods
40male Sprague-Dawley rats were randomly divided into five groups:buflomedil pyridoxal phosphate (BPP) group; buflomedil+VitB6group; buflomedil group; Met group; the controlled group. At the end of the8th weeks, get blood plasma and unilateral carotid artery to measure the concentration of homocysteine and superoxide dismutase, the protein expression of endothelial nitric oxide synthase.
Results
1.The Hcy concentration of Met group was significantly higher than controlled group(P<0.01), the Hcy concentration of the BPP, buflomedil+vitamin B6, buflomedil group was lower than Met group(P<0.01), the Hcy concentration of BPP group was significantly lower than buflomedil+vitamin B6group(P<0.01), close to the controlled group(P>0.05).
2.The SOD concentration of Met group was significantly lower than controlled group(P<0.01), the SOD concentration of the BPP, buflomedil+vitamin B6, buflomedil group was higher than Met group(P <0.05); the SOD concentration of BPP group was close to buflomedil+vitamin B6group.
3. The eNOS expression of Met group was significantly lower than controlled group(P<0.01), the eNOS expression of the BPP, buflomedil+vitamin B6, buflomedil group was higher than Met group(P<0.01), the eNOS expression of BPP group was significantly higher than buflomedil+vitamin B6group(P<0.01), close to the controlled group(P>0.05).
4. The eNOS expression was negatively correlated with Hcy concentration.
Conclusions
1. Buflomedil pyridoxal phosphate, buflomedil+vitamin B6, buflomedil can all decrease plasma Hcy level, and may prevent the negative effect of Hcy to SOD, eNOS.
2. Homocysteine can reduce NO production through suppressing the expression of eNOS.
3. The influence of buflomedil pyridoxal phosphate on the biological effect of hyperhomocysteinemia was significant, and better than buflomedil+vitamin B6.
引文
[1]Bolander-Gouaille, Christina. Focus on Homocysteine and the Vitamins:Involved in its metabolism [M]. New York:Springer,2002.262
[2]高霖,唐朝枢.高同型半胱氨酸致动脉粥样硬化的细胞分子机制[J].生理科学进展,2002,33：335-338
[3]McCully K S. homocysteine and vascular disease[J]. Nat Med,1996,2(4):386-389
[4]Herrmann W, Quast S, et al. Hyperhomocysteinemia in high-aged subjects: relation of B-vitamins, folic acid, renal function and the methylenetetrahy drofolate reducase mutation [J]. Atherosclerosis,1999,144:91-101
[5]MJ Mooren, M Wouters, HJ Blom, et al. Hormone replacement therapy may reduce high serum homocysteine in postmenopausal women[J]. European Journal of Clinical Investigation,1995,24,:733-736
[6]B Hultberg, A Andersson, G Sterner, et al. Plasma homocysteine in renal failure[J]. Clinical nephrology,1993,40(4):230-235
[7]Frosst P, Blom H J, Milos R,et al. Acandidate genetic risk factor for vascular disease:a common mutation in methylenetetrahydrofolate reduetase. Nature Geneties,1995,10:111-113
[8]Pezzini A, Del Zot to E, Archetti S, et al. Plasma concentration, C677 TMTHFR genotype, and 844ins68bp CBS genotype in young adults with spontaneous cervical artery dissection and at herothromboric stroke[J]. Stroke, 2002,33 (3):664-669
[9]Robinson K, Arheat K, Refsum H, et al. Low circulating folate and vitamin B6 concentrations:risk factors for stroke, peripheral vascular disease, and coronary artery disease[J]. Circulation,1998,97:437-443
[10]Kazushi Tsuda, Ichiro Nishio, Peter J, et al. Homocysteine, Vitamin B6, and Endothelial Dysfunction in Circulatory [J]. Stroke,2004,35:35-43
[11]Nygard O, Vollset S E, Refsum H, et al. Total plasma homocysteine and cardiovascular risk profile[J]. JAMA,1995,274(19):1526-1533
[12]Wilcken D, Wilcken B. The pathogenesis of coronary artery disease. A possible role for methionine metabolism[J]. J Clin Invest,1976,6:1079-1082
[13]LE Brattstrom, JE Hardebo, BL Hultberg. Moderate homocysteinemia--a possible risk factor for arteriosclerotic cerebrovascular disease[J]. Stroke,1984, 15:1012-1016
[14]Boyce M, Bryant K F, Jousse C. A selective inhibitor of elF2alpha dephosphorylation protects cells from ER stress [J]. Science,2005,307 (5711): 935-939
[15]Ji C, Kap lowitz N. Hyperhomocysteinemia, endoplasmic reticulum stress and alcoholic liver injury [J]. World J Gastroenterol,2004,10 (2):1699-1708
[16]Rodgers G M, Kane WH. Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator[J]. JClinInvest,1986,77(6):1909-1916
[17]Undas A, Williams EB, Butenas S, et al. Homocysteine inhibits inactivation of factor Va by activated protein C[J].Biol Chem,2001,276(6):4389-4397
[18]Leoncini G, Bruzzese D, Signorello M G. Activation of p38MAPK in ase /cPLA2 pathway in homocysteine-treated plateletes[J]. JThrombHasemost,2006, 4(1):209-216
[19]陈景开,周辽军,赵秋良.高同型半胱氨酸血症与LDL氧化修饰及动脉粥样硬化的关系[J].解放军医学杂志,2001,26(5)：327-329
[20]Hopkins PN, Wull, Hunt DC, et al. Lipoprotein (a) interactions with lipid and nonlipid risk factors in early familial coronary artery disease[J]. Arterioscler Thomb VascuBiol,1997,17(11):2783-2792
[21]Young PB,Kennedy S, Molloy AM,et al. Lipid peroxidation induced in vivo by hyperhomocysteinemia in pigs[J].Atherosclerosis,1997,129(1):67-71
[22]Tsai J C, Wang H, Perrella M A, et al. Induction of cyclin A gene expression by homocysteine in vascular smooth muscle cells[J]. JClinInvest,1996,97(1):146-153
[23]Dalton ML, Gadson PF, Wrenn PW, et al. Homocysteine signal cascade: production of phospholipids, activation of protein kinase C, and the induction of c-fos and c-myb in smoothmuscle cells[J]. FASEBJ,1997,11(8):703-711
[24]Baumbach GL, Sigmund CD, Bottiglieri T,et al. Structure of cerebral arterioles in cystathionine beta-synthase-deficientmice[J]. CircRes,2002,91(10):931-937
[25]Postea O, Krotz F, Henger A, et al. Stereospecific and redox-sensitive increase in monocyte adhesion to endothelial cells by homocysteine [J]. Arterioscler Thromb Vase Biol,2006,26(3):508-513
[26]Glushchenko AV, Jacobsen DW. Molecular targeting of proteins by L-homocysteine mechanistic implications for vascular disease[J]. Antioxid Redox Signal,2007,9(11):1883-1898
[27]Bogdan N, Manolescul, Eliza Oprea, et al. Homocysteine and vitamin therapy in stroke prevention and treatment:a review[J]. Acta Biochim Pol,2010,57(4):467-77
[28]Warren C J. What is homocysteine[J]. AM J Nurs,1999,99(10):39-41
[29]Lewerin C, Nilsson Ehle, H Matousek, et al. Reduction of plasma homocysteine and serum methylmalonate concentrations in apparently healthy elderly subjects after treatment with folic acid, vitamin B12 and vitamin B6:a randomised trial[J]. JAMA,2004,291:565-575
[30]Diamantopoulos EJ, Grigoriadou M, Ifanti G, et al. Clinical and hemorheological effects of buflomedil in diabetic subjects with intermittent claudication[J]. Int Angiol.2001 Dec;20(4):337-444.
[31]Paolo Colomboa, Ruggero Bettinia, Nikolaos A.Observation of swelling process and diffusion front position during swelling in hydroxypropyl methyl cellulose (HPMC) matrices containing a soluble drug[J]. Journal of Controlled Release,1999,61:83-91
[32]J. Siepmanna, N.A. Peppasb.Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC)[J]. Advanced Drug Delivery Reviews,2001,59:139-157
[33]Paolo Colomboa, Ruggero Bettinia, Pier Luigi Catellania, et al. Drug volume fraction profile in the gel phase and drug release kinetics in hydroxypropylmethyl cellulose matrices containing a soluble drug[J]. European Journal of Pharmaceutical Sciences 1999,9:33-40
[34]Elena Losi, Ruggero Bettini, Patrizia Santi, et al. Assemblage of novel release modules for the development of adaptable drug[J]. Journal of Controlled Release,2006,11:212-218
[35]Rodrigo R, Passalacqua W, Araya J. Implications of oxidative stress and homocysteine in the pathophysiology of essential hypertension[J]. Cardiovasc Pharmacol,2003,42(4):453-61
[35]DerrickL S, ErinK A, Charles W B, et al. Prothrombotic and pre-oxidant effects of diet-induced hyperhomocysteinemia[J]. Thrombosis Research,2007,120(1): 117-126
[36]Weiss N, Keller C, Hoffmann U, et al. Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia[J]. VaseMed,2002,7(3):227-239
[37]A. F. Perna, D. Ingrosso, N. G. De Santo. Homocysteine and oxidative stress[J]. Amino Acids,2003,3:409-427
[38]Frank M. Faraci, Steven R. Lentz. Hyperhomocysteinemia, Oxidative Stress, and Cerebral Vascular Dysfunction[J]. Stroke 2004,35:345-347.
[39]Neetu Tyagi, Kara C. Sedoris, Mesia Steed, et al. Mechanisms of homocysteine-induced oxidative stress[J]. Physiol Heart Circ Physiol,2005,289:2649-2656
[40]Widner B, Enzinger C, Laich A, et al. Hyperhomocysteinemia, pteridines and oxidative stress[J]. Curr Drug Metab,2002,3(2):225-232
[41]Eugene J. Rogers, ShanShan Chen, Amy Chan. Folate Deficiency and Plasma Homocysteine during Increased Oxidative Stress[J].N Engl J Med 2007,357:421-422
[42]Upcherch G R, Welch C A, Fabian A J, et al. Homocysteine decrease bioavailabe nitric oxide by a mechanism involving glutathione peroxidase[J]. J Biol Chem,1997,27:17012-17020
[43]J. RACEK, H. RUSNAKOVA, L. TREFIL, et al. The Influence of Folate and Antioxidants on Homocysteine Levels and Oxidative Stress in Patients with Hyperlipidemia and Hyperhomocysteinemia[J]. Physiol. Res,2005,54:87-95
[44]Tawkol A, Omaland T, et al. Hyperhomocysteinemia is associated with impaired endothelium-dependent vasodilation in humans[J]. Circulation,1997,95(5):1119-1121
[45]Olaf Stanger, Martin Weger. Interactions of homocysteine, Nitric Oxide, Folate and Radicals in the progressively damaged endothelium[J]. Clin Chem Lab Med 2003,41(11):1444-1454
[46]Seon-Jin Lee, Ki-Mo Kim. Nitric Oxide Inhibition of Homocysteine-induced Human Endothelial Cell Apoptosis by Down-regulation of p53-dependent Noxa Expression through the Formation of S-Nitrosohomocysteine[J]. The Journal of Biological Chemistry,2005,15,5781-5788
[47]Markus C, Stiihlinger, Philip S. Tsao, et al. Homocysteine impairs the Nitric Oxide Synthase Pathway[J]. Circulation,2001,104:2569-2575
[48]Welch GN, Upchurch GR Jr, Farivar RS, et al. Homocysteine-induced nitric oxide production in vascular smooth-muscle cells by NF-kappa B-dependent transcriptional activation of Nos2[J]. Proc Assoc Am Physicians,1998,110(1): 22-31
[49]马向红,黄体刚,周丽娟.同型半胱氨酸对大鼠内皮细胞分泌一氧化氮、血管紧张素Ⅱ、内皮素的影响[J].中国心血管杂志,1998,3(5)：344-348
[50]Xiaohui Zhang, Hong Li, Haoli Jin, et al. Effects of homocysteine on endothelial nitric oxide production[J]. AJP-Renal Physiol,2000,279,671-678
[1]Bolander-Gouaille, Christina. Focus on Homocysteine and the Vitamins:Involved in its metabolism [M]. New York:Springer,2002.262
[2]高霖,唐朝枢.高同型半胱氨酸致动脉粥样硬化的细胞分子机制[J].生理科学进展,2002,33：335-338
[3]McCully K S. homocysteine and vascular disease[J]. Nat Med,1996,2(4):386-389
[4]Frosst P, Blom H J, Milos R,et al. Acandidate genetic risk factor for vascular disease:a common mutation in methylenetetrahydrofolate reduetase. Nature Geneties,1995,10:111-113
[5]Brattstrom L, Wilcken D E, Ohrvik J, et al. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease:the result of ameta-analysis[J].Circulation,1998,98(23):2520-2526
[6]Pezzini A, Del Zot to E, Archetti S, et al. Plasma concentration, C677 TMTHFR genotype, and 844ins68bp CBS genotype in young adults with spontaneous cervical artery dissection and at herothromboric stroke [J]. Stroke, 2002,33 (3):664-669
[7]McCully K S. Vascular pathology of homocysteinemia:implications for the pathogenesis of arteriosclerosis [J]. Am J Pat hol,1969,56 (1):111-128
[8]Robinson K, Arheat K, Refsum H, et al. Low circulating folate and vitamin B6 concentrations:risk factors for stroke, peripheral vascular disease, and coronary artery disease[J]. Circulation,1998,97:437-443
[9]Kazushi Tsuda, Ichiro Nishio, Peter J, et al. Homocysteine, Vitamin B6, and Endothelial Dysfunction in Circulatory [J]. Stroke,2004,35:35-43
[10]Wouters M G, Moorrees M T, Vander Mooren MJ, et al. Plasma homocysteine and menopausal status[J]. Eur Jailllnvest,1995,25:801-805
[11]MJ Mooren, M Wouters, HJ Blom, et al. Hormone replacement therapy may reduce high serum homocysteine in postmenopausal women[J]. European Journal of Clinical Investigation,1995,24,:733-736
[12]Amores-Sanchez MI, Aedina MA. Method for the determination of plasma total homocysteine[J]. Clin Chem Lad Med,2000,38(3):199-204
[13]B Hultberg, A Andersson, G Sterner, et al. Plasma homocysteine in renal failure[J]. Clinical nephrology,1993,40(4):230-235
[14]Ueland P M, Refsum H, Brattsrom L, et al. Plasma homocysteine and cardiovascular disease[A]. In:Francis RB Jr, editor. Atherosclerotic Cardiovascular Disease, Homostasis, and Endothelial Function[M]. New York: Marcel Dekker,1992.183-236
[15]Welch G N, Loscalzo J. Homocysteine and atherothrombosis[J]. N Engl J Med,1998,9:338(15):1042-1050
[16]Nygard O, Vollset S E, Refsum H, et al. Total plasma homocysteine and cardiovascular risk profile[J]. JAMA,1995,274(19):1526-1533
[17]Wilcken D, Wilcken B. The pathogenesis of coronary artery disease. A possible role for methionine metabolism[J]. J Clin Invest,1976,6:1079-1082
[18]LE Brattstrom, JE Hardebo, BL Hultberg. Moderate homocysteinemia--a possible risk factor for arteriosclerotic cerebrovascular disease[J]. Stroke,1984, 15:1012-1016.
[19]DerrickL S, ErinK A, Charles W B, et al. Prothrombotic and pre-oxidant effects of diet-induced hyperhomocysteinemia[J]. Thrombosis Research,2007,120(1): 117-126
[20]Weiss N, Keller C, Hoffmann U, et al. Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia[J]. VaseMed,2002,7(3):227-239
[21]A. F. Perna, D. Ingrosso, N. G. De Santo. Homocysteine and oxidative stress[J]. Amino Acids,2003,3:409-427
[22]Frank M. Faraci, Steven R. Lentz. Hyperhomocysteinemia, Oxidative Stress, and Cerebral Vascular Dysfunction[J]. Stroke 2004,35:345-347.
[23]Neetu Tyagi, Kara C. Sedoris, Mesia Steed, et al. Mechanisms of homocysteine-induced oxidative stress[J]. Physiol Heart Circ Physiol,2005,289:2649-2656
[24]Widner B, Enzinger C, Laich A, et al. Hyperhomocysteinemia, pteridines and oxidative stress[J]. Curr Drug Metab,2002,3(2):225-232
[25]Eugene J. Rogers, ShanShan Chen, Amy Chan. Folate Deficiency and Plasma Homocysteine during Increased Oxidative Stress [J].N Engl J Med 2007,357:421-422
[26]Upcherch G R, Welch C A, Fabian A J, et al. Homocysteine decrease bioavailabe nitric oxide by a mechanism involving glutathione peroxidase[J]. J Biol Chem,1997,27:17012-17020
[27]J. RACEK, H. RUSNAKOVA, L. TREFIL, et al. The Influence of Folate and Antioxidants on Homocysteine Levels and Oxidative Stress in Patients with Hyperlipidemia and Hyperhomocysteinemia[J]. Physiol. Res,2005,54:87-95
[28]Upcherch G R, Welch C A, Fabian A J, et al. Homocysteine decrease bioavailabe nitric oxide by a mechanism involving glutathione peroxidase[J]. J Biol Chem,1997,27:17012-17020
[29]Boyce M, Bryant K F, Jousse C. A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress [J]. Science,2005,307 (5711): 935-939
[30]Ji C, Kap lowitz N. Hyperhomocysteinemia, endoplasmic reticulum stress and alcoholic liver injury [J]. World J Gastroenterol,2004,10 (2):1699-1708
[31]Tawkol A, Omaland T, et al. Hyperhomocysteinemia is associated with impaired endothelium-dependent vasodilation in humans [J]. Circulation,1997, 95(5):1119-1121
[32]Olaf Stanger, Martin Weger. Interactions of homocysteine, Nitric Oxide, Folate and Radicals in the progressively damaged endothelium[J]. Clin Chem Lab Med 2003,41(11):1444-1454
[33]Seon-Jin Lee, Ki-Mo Kim. Nitric Oxide Inhibition of Homocysteine-induced Human Endothelial Cell Apoptosis by Down-regulation of p53-dependent Noxa Expression through the Formation of S-Nitrosohomocysteine[J]. The Journal of Biological Chemistry,2005,15,5781-5788
[34]Markus C, Stiihlinger, Philip S. Tsao,et al. Homocysteine impairs the Nitric Oxide Synthase Pathway[J]. Circulation,2001,104:2569-2575
[35]Welch GN, Upchurch GR Jr, Farivar RS, et al. Homocysteine-induced nitric oxide production in vascular smooth-muscle cells by NF-kappa B-dependent transcriptional activation of Nos2[J]. Proc Assoc Am Physicians,1998, 110(1):22-31
[36]马向红,黄体刚,周丽娟.同型半胱氨酸对大鼠内皮细胞分泌一氧化氮、血管紧张素Ⅱ、内皮素的影响[J].中国心血管杂志,1998,3(5)：344-348
[37]Xiaohui Zhang, Hong Li, Haoli Jin, et al. Effects of homocysteine on endothelial nitric oxide production[J]. AJP-Renal Physiol,2000,279,671-678
[38]Rodgers G M,Kane WH. Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator[J]. JClinInvest,1986,77(6):1909-1916
[39]Undas A, Williams EB, Butenas S,et al. Homocysteine inhibits inactivation of factor Va by activated protein C[J].Biol Chem,2001,276(6):4389-4397
[40]Leoncini G, Bruzzese D, Signorello M G. Activation of p38MAPK in ase /cPLA2 pathway in homocysteine-treated plateletes[J]. JThrombHasemost,2006, 4(1):209-216
[40]陈景开,周辽军,赵秋良.高同型半胱氨酸血症与LDL氧化修饰及动脉粥样硬化的关系[J].解放军医学杂志,2001,26(5)：327-329
[41]Hopkins PN, Wull, Hunt DC, et al. Lipoprotein (a) interactions with lipid and nonlipid risk factors in early familial coronary artery disease[J]. Arterioscler Thomb VascuBiol,1997,17(11):2783-2792
[42]Young PB,Kennedy S, Molloy AM,et al. Lipid peroxidation induced in vivo by hyperhomocysteinemia in pigs[J].Atherosclerosis,1997,129(1):67-71
[43]Tsai J C, Wang H, Perrella M A, et al. Induction of cyclin A gene expression by homocysteine in vascular smooth muscle cells[J]. JClinInvest,1996,97(1):146-153
[44]Dalton ML, Gadson PF, Wrenn PW, et al. Homocysteine signal cascade: production of phospholipids, activation of protein kinase C, and the induction of c-fos and c-myb in smoothmuscle cells[J]. FASEBJ,1997,11(8):703-711
[45]Baumbach GL, Sigmund CD, Bottiglieri T,et al. Structure of cerebral arterioles in cystathionine beta-synthase-deficientmice[J]. CircRes,2002,91(10):931-937
[46]Postea O, Krotz F, Henger A, et al. Stereospecific and redox-sensitive increase in monocyte adhesion to endothelial cells by homocysteine [J]. Arterioscler Thromb Vase Biol,2006,26(3):508-513
[47]Glushchenko AV, Jacobsen DW. Molecular targeting of proteins by L-homocysteine mechanistic implications for vascular disease[J]. Antioxid Redox Signal,2007,9(11):1883-1898
[48]Jakubowski, Hieronim. Protein homocysteinylation:possible mechanism underlying pathological consequences of elevated homocysteine levels [J]. FASEB J,1999(13):2277-2283
[49]Kostner G M, Steinmeta A. Standardization of Lp(a) measurement[J]. Clin Genet,1997,52(2):393-397
[50]Marcovina S M, Albers J J, Scanu A M, et al. Use of a reference maerial proposed by the International Federation of Clinical Chemistry and Laboratory Medicine to evaluate analytical methods for the determination of plasma lipoprotein(a)[J]. Clin Chem,2000,46(12): 1956-1967
[51]Frantzen F, Faaren A L, Alfheim I, et al. Enzyme conversion immunoassay for determining total homocysteine in plasma or serum[J]. Clin Chem, 1998,44(2): 311-316
[52]Amores-Sanchez M I, Medina M A. Method for the determination of plasma total homocysteine [J]. Clin Chem Lad Med,2000,38(3);199-204
[53]Guo H, Lee JD, Ueda ,et al. Hyperhomocysteinaemia &folic and supplementation in patient s with high risk of coronary artery disease[J ] . Indian J Med Res ,2004,119 (1): 33-37.
[54]Lobo A, Naso A, Arheart K, et al. Reduction of homocysteine levels in coronary artery disease by low- dose folic acid combined with vitamins B6 and B12 [ J] . AM J Cardiol 1999,83(6):821-825.
[55]Anderson JL, J ensen KR, Caelquist J , et al. Effect of folic acidfortification of food on homocysteine - related mortality[J]. Am J Med,2004,l 16 (2):158-164
[56]Narin F, Narin N, Akcakus M, et al. The effect of folic acid, vitamin B6 and vitamin B12 no the homocysteine levels in rabbit s fed by methionine - enriched diets[J ]. Tohoku Journal of Experimental Med.icine, 2002,198 (2): 99-105.
[57]Steenge GR, Verhoef P, Katan MB, et al. Betaine supplementation lowers plasma homocysteine in healthy men and women[J ]. J Nut r,2003,133(5): 1291-1295.
[58]Sakamoto A, Sakura N. Limited effectiveness of betaine therapy for cystathionine beta synthase deficiency [J]. Pediatr Int, 2003,45:333-338.
[59]石彦荣,唐朝.牛磺酸的跨细胞膜转运[J].国外医学生理、病理科学与临床分册,2001,61：553-456.
[60]Chang L, Xu J, Yu F, et al. Taurine protected myocardial mitiochondria injury induced by hyperhomocysteinemia in rats[J]. Amino Acids, 2004,27:37-48.
[61]Zhao W, Zhang J, Lu Y, et al. The vasorelaxnt effect of H2S as a novel endogenous gaseous K(ATP) channel opener[J]. EMBO J, 2001,20:6008-6016.
[2]高霖,唐朝枢.高同型半胱氨酸致动脉粥样硬化的细胞分子机制[J].生理科学进展,2002,33：335-338
[3]McCully K S. homocysteine and vascular disease[J]. Nat Med,1996,2(4):386-389
[4]Herrmann W, Quast S, et al. Hyperhomocysteinemia in high-aged subjects: relation of B-vitamins, folic acid, renal function and the methylenetetrahy drofolate reducase mutation [J]. Atherosclerosis,1999,144:91-101
[5]MJ Mooren, M Wouters, HJ Blom, et al. Hormone replacement therapy may reduce high serum homocysteine in postmenopausal women[J]. European Journal of Clinical Investigation,1995,24,:733-736
[6]B Hultberg, A Andersson, G Sterner, et al. Plasma homocysteine in renal failure[J]. Clinical nephrology,1993,40(4):230-235
[7]Frosst P, Blom H J, Milos R,et al. Acandidate genetic risk factor for vascular disease:a common mutation in methylenetetrahydrofolate reduetase. Nature Geneties,1995,10:111-113
[8]Pezzini A, Del Zot to E, Archetti S, et al. Plasma concentration, C677 TMTHFR genotype, and 844ins68bp CBS genotype in young adults with spontaneous cervical artery dissection and at herothromboric stroke[J]. Stroke, 2002,33 (3):664-669
[9]Robinson K, Arheat K, Refsum H, et al. Low circulating folate and vitamin B6 concentrations:risk factors for stroke, peripheral vascular disease, and coronary artery disease[J]. Circulation,1998,97:437-443
[10]Kazushi Tsuda, Ichiro Nishio, Peter J, et al. Homocysteine, Vitamin B6, and Endothelial Dysfunction in Circulatory [J]. Stroke,2004,35:35-43
[11]Nygard O, Vollset S E, Refsum H, et al. Total plasma homocysteine and cardiovascular risk profile[J]. JAMA,1995,274(19):1526-1533
[12]Wilcken D, Wilcken B. The pathogenesis of coronary artery disease. A possible role for methionine metabolism[J]. J Clin Invest,1976,6:1079-1082
[13]LE Brattstrom, JE Hardebo, BL Hultberg. Moderate homocysteinemia--a possible risk factor for arteriosclerotic cerebrovascular disease[J]. Stroke,1984, 15:1012-1016
[14]Boyce M, Bryant K F, Jousse C. A selective inhibitor of elF2alpha dephosphorylation protects cells from ER stress [J]. Science,2005,307 (5711): 935-939
[15]Ji C, Kap lowitz N. Hyperhomocysteinemia, endoplasmic reticulum stress and alcoholic liver injury [J]. World J Gastroenterol,2004,10 (2):1699-1708
[16]Rodgers G M, Kane WH. Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator[J]. JClinInvest,1986,77(6):1909-1916
[17]Undas A, Williams EB, Butenas S, et al. Homocysteine inhibits inactivation of factor Va by activated protein C[J].Biol Chem,2001,276(6):4389-4397
[18]Leoncini G, Bruzzese D, Signorello M G. Activation of p38MAPK in ase /cPLA2 pathway in homocysteine-treated plateletes[J]. JThrombHasemost,2006, 4(1):209-216
[19]陈景开,周辽军,赵秋良.高同型半胱氨酸血症与LDL氧化修饰及动脉粥样硬化的关系[J].解放军医学杂志,2001,26(5)：327-329
[20]Hopkins PN, Wull, Hunt DC, et al. Lipoprotein (a) interactions with lipid and nonlipid risk factors in early familial coronary artery disease[J]. Arterioscler Thomb VascuBiol,1997,17(11):2783-2792
[21]Young PB,Kennedy S, Molloy AM,et al. Lipid peroxidation induced in vivo by hyperhomocysteinemia in pigs[J].Atherosclerosis,1997,129(1):67-71
[22]Tsai J C, Wang H, Perrella M A, et al. Induction of cyclin A gene expression by homocysteine in vascular smooth muscle cells[J]. JClinInvest,1996,97(1):146-153
[23]Dalton ML, Gadson PF, Wrenn PW, et al. Homocysteine signal cascade: production of phospholipids, activation of protein kinase C, and the induction of c-fos and c-myb in smoothmuscle cells[J]. FASEBJ,1997,11(8):703-711
[24]Baumbach GL, Sigmund CD, Bottiglieri T,et al. Structure of cerebral arterioles in cystathionine beta-synthase-deficientmice[J]. CircRes,2002,91(10):931-937
[25]Postea O, Krotz F, Henger A, et al. Stereospecific and redox-sensitive increase in monocyte adhesion to endothelial cells by homocysteine [J]. Arterioscler Thromb Vase Biol,2006,26(3):508-513
[26]Glushchenko AV, Jacobsen DW. Molecular targeting of proteins by L-homocysteine mechanistic implications for vascular disease[J]. Antioxid Redox Signal,2007,9(11):1883-1898
[27]Bogdan N, Manolescul, Eliza Oprea, et al. Homocysteine and vitamin therapy in stroke prevention and treatment:a review[J]. Acta Biochim Pol,2010,57(4):467-77
[28]Warren C J. What is homocysteine[J]. AM J Nurs,1999,99(10):39-41
[29]Lewerin C, Nilsson Ehle, H Matousek, et al. Reduction of plasma homocysteine and serum methylmalonate concentrations in apparently healthy elderly subjects after treatment with folic acid, vitamin B12 and vitamin B6:a randomised trial[J]. JAMA,2004,291:565-575
[30]Diamantopoulos EJ, Grigoriadou M, Ifanti G, et al. Clinical and hemorheological effects of buflomedil in diabetic subjects with intermittent claudication[J]. Int Angiol.2001 Dec;20(4):337-444.
[31]Paolo Colomboa, Ruggero Bettinia, Nikolaos A.Observation of swelling process and diffusion front position during swelling in hydroxypropyl methyl cellulose (HPMC) matrices containing a soluble drug[J]. Journal of Controlled Release,1999,61:83-91
[32]J. Siepmanna, N.A. Peppasb.Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC)[J]. Advanced Drug Delivery Reviews,2001,59:139-157
[33]Paolo Colomboa, Ruggero Bettinia, Pier Luigi Catellania, et al. Drug volume fraction profile in the gel phase and drug release kinetics in hydroxypropylmethyl cellulose matrices containing a soluble drug[J]. European Journal of Pharmaceutical Sciences 1999,9:33-40
[34]Elena Losi, Ruggero Bettini, Patrizia Santi, et al. Assemblage of novel release modules for the development of adaptable drug[J]. Journal of Controlled Release,2006,11:212-218
[35]Rodrigo R, Passalacqua W, Araya J. Implications of oxidative stress and homocysteine in the pathophysiology of essential hypertension[J]. Cardiovasc Pharmacol,2003,42(4):453-61
[35]DerrickL S, ErinK A, Charles W B, et al. Prothrombotic and pre-oxidant effects of diet-induced hyperhomocysteinemia[J]. Thrombosis Research,2007,120(1): 117-126
[36]Weiss N, Keller C, Hoffmann U, et al. Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia[J]. VaseMed,2002,7(3):227-239
[37]A. F. Perna, D. Ingrosso, N. G. De Santo. Homocysteine and oxidative stress[J]. Amino Acids,2003,3:409-427
[38]Frank M. Faraci, Steven R. Lentz. Hyperhomocysteinemia, Oxidative Stress, and Cerebral Vascular Dysfunction[J]. Stroke 2004,35:345-347.
[39]Neetu Tyagi, Kara C. Sedoris, Mesia Steed, et al. Mechanisms of homocysteine-induced oxidative stress[J]. Physiol Heart Circ Physiol,2005,289:2649-2656
[40]Widner B, Enzinger C, Laich A, et al. Hyperhomocysteinemia, pteridines and oxidative stress[J]. Curr Drug Metab,2002,3(2):225-232
[41]Eugene J. Rogers, ShanShan Chen, Amy Chan. Folate Deficiency and Plasma Homocysteine during Increased Oxidative Stress[J].N Engl J Med 2007,357:421-422
[42]Upcherch G R, Welch C A, Fabian A J, et al. Homocysteine decrease bioavailabe nitric oxide by a mechanism involving glutathione peroxidase[J]. J Biol Chem,1997,27:17012-17020
[43]J. RACEK, H. RUSNAKOVA, L. TREFIL, et al. The Influence of Folate and Antioxidants on Homocysteine Levels and Oxidative Stress in Patients with Hyperlipidemia and Hyperhomocysteinemia[J]. Physiol. Res,2005,54:87-95
[44]Tawkol A, Omaland T, et al. Hyperhomocysteinemia is associated with impaired endothelium-dependent vasodilation in humans[J]. Circulation,1997,95(5):1119-1121
[45]Olaf Stanger, Martin Weger. Interactions of homocysteine, Nitric Oxide, Folate and Radicals in the progressively damaged endothelium[J]. Clin Chem Lab Med 2003,41(11):1444-1454
[46]Seon-Jin Lee, Ki-Mo Kim. Nitric Oxide Inhibition of Homocysteine-induced Human Endothelial Cell Apoptosis by Down-regulation of p53-dependent Noxa Expression through the Formation of S-Nitrosohomocysteine[J]. The Journal of Biological Chemistry,2005,15,5781-5788
[47]Markus C, Stiihlinger, Philip S. Tsao, et al. Homocysteine impairs the Nitric Oxide Synthase Pathway[J]. Circulation,2001,104:2569-2575
[48]Welch GN, Upchurch GR Jr, Farivar RS, et al. Homocysteine-induced nitric oxide production in vascular smooth-muscle cells by NF-kappa B-dependent transcriptional activation of Nos2[J]. Proc Assoc Am Physicians,1998,110(1): 22-31
[49]马向红,黄体刚,周丽娟.同型半胱氨酸对大鼠内皮细胞分泌一氧化氮、血管紧张素Ⅱ、内皮素的影响[J].中国心血管杂志,1998,3(5)：344-348
[50]Xiaohui Zhang, Hong Li, Haoli Jin, et al. Effects of homocysteine on endothelial nitric oxide production[J]. AJP-Renal Physiol,2000,279,671-678
[1]Bolander-Gouaille, Christina. Focus on Homocysteine and the Vitamins:Involved in its metabolism [M]. New York:Springer,2002.262
[2]高霖,唐朝枢.高同型半胱氨酸致动脉粥样硬化的细胞分子机制[J].生理科学进展,2002,33：335-338
[3]McCully K S. homocysteine and vascular disease[J]. Nat Med,1996,2(4):386-389
[4]Frosst P, Blom H J, Milos R,et al. Acandidate genetic risk factor for vascular disease:a common mutation in methylenetetrahydrofolate reduetase. Nature Geneties,1995,10:111-113
[5]Brattstrom L, Wilcken D E, Ohrvik J, et al. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease:the result of ameta-analysis[J].Circulation,1998,98(23):2520-2526
[6]Pezzini A, Del Zot to E, Archetti S, et al. Plasma concentration, C677 TMTHFR genotype, and 844ins68bp CBS genotype in young adults with spontaneous cervical artery dissection and at herothromboric stroke [J]. Stroke, 2002,33 (3):664-669
[7]McCully K S. Vascular pathology of homocysteinemia:implications for the pathogenesis of arteriosclerosis [J]. Am J Pat hol,1969,56 (1):111-128
[8]Robinson K, Arheat K, Refsum H, et al. Low circulating folate and vitamin B6 concentrations:risk factors for stroke, peripheral vascular disease, and coronary artery disease[J]. Circulation,1998,97:437-443
[9]Kazushi Tsuda, Ichiro Nishio, Peter J, et al. Homocysteine, Vitamin B6, and Endothelial Dysfunction in Circulatory [J]. Stroke,2004,35:35-43
[10]Wouters M G, Moorrees M T, Vander Mooren MJ, et al. Plasma homocysteine and menopausal status[J]. Eur Jailllnvest,1995,25:801-805
[11]MJ Mooren, M Wouters, HJ Blom, et al. Hormone replacement therapy may reduce high serum homocysteine in postmenopausal women[J]. European Journal of Clinical Investigation,1995,24,:733-736
[12]Amores-Sanchez MI, Aedina MA. Method for the determination of plasma total homocysteine[J]. Clin Chem Lad Med,2000,38(3):199-204
[13]B Hultberg, A Andersson, G Sterner, et al. Plasma homocysteine in renal failure[J]. Clinical nephrology,1993,40(4):230-235
[14]Ueland P M, Refsum H, Brattsrom L, et al. Plasma homocysteine and cardiovascular disease[A]. In:Francis RB Jr, editor. Atherosclerotic Cardiovascular Disease, Homostasis, and Endothelial Function[M]. New York: Marcel Dekker,1992.183-236
[15]Welch G N, Loscalzo J. Homocysteine and atherothrombosis[J]. N Engl J Med,1998,9:338(15):1042-1050
[16]Nygard O, Vollset S E, Refsum H, et al. Total plasma homocysteine and cardiovascular risk profile[J]. JAMA,1995,274(19):1526-1533
[17]Wilcken D, Wilcken B. The pathogenesis of coronary artery disease. A possible role for methionine metabolism[J]. J Clin Invest,1976,6:1079-1082
[18]LE Brattstrom, JE Hardebo, BL Hultberg. Moderate homocysteinemia--a possible risk factor for arteriosclerotic cerebrovascular disease[J]. Stroke,1984, 15:1012-1016.
[19]DerrickL S, ErinK A, Charles W B, et al. Prothrombotic and pre-oxidant effects of diet-induced hyperhomocysteinemia[J]. Thrombosis Research,2007,120(1): 117-126
[20]Weiss N, Keller C, Hoffmann U, et al. Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia[J]. VaseMed,2002,7(3):227-239
[21]A. F. Perna, D. Ingrosso, N. G. De Santo. Homocysteine and oxidative stress[J]. Amino Acids,2003,3:409-427
[22]Frank M. Faraci, Steven R. Lentz. Hyperhomocysteinemia, Oxidative Stress, and Cerebral Vascular Dysfunction[J]. Stroke 2004,35:345-347.
[23]Neetu Tyagi, Kara C. Sedoris, Mesia Steed, et al. Mechanisms of homocysteine-induced oxidative stress[J]. Physiol Heart Circ Physiol,2005,289:2649-2656
[24]Widner B, Enzinger C, Laich A, et al. Hyperhomocysteinemia, pteridines and oxidative stress[J]. Curr Drug Metab,2002,3(2):225-232
[25]Eugene J. Rogers, ShanShan Chen, Amy Chan. Folate Deficiency and Plasma Homocysteine during Increased Oxidative Stress [J].N Engl J Med 2007,357:421-422
[26]Upcherch G R, Welch C A, Fabian A J, et al. Homocysteine decrease bioavailabe nitric oxide by a mechanism involving glutathione peroxidase[J]. J Biol Chem,1997,27:17012-17020
[27]J. RACEK, H. RUSNAKOVA, L. TREFIL, et al. The Influence of Folate and Antioxidants on Homocysteine Levels and Oxidative Stress in Patients with Hyperlipidemia and Hyperhomocysteinemia[J]. Physiol. Res,2005,54:87-95
[28]Upcherch G R, Welch C A, Fabian A J, et al. Homocysteine decrease bioavailabe nitric oxide by a mechanism involving glutathione peroxidase[J]. J Biol Chem,1997,27:17012-17020
[29]Boyce M, Bryant K F, Jousse C. A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress [J]. Science,2005,307 (5711): 935-939
[30]Ji C, Kap lowitz N. Hyperhomocysteinemia, endoplasmic reticulum stress and alcoholic liver injury [J]. World J Gastroenterol,2004,10 (2):1699-1708
[31]Tawkol A, Omaland T, et al. Hyperhomocysteinemia is associated with impaired endothelium-dependent vasodilation in humans [J]. Circulation,1997, 95(5):1119-1121
[32]Olaf Stanger, Martin Weger. Interactions of homocysteine, Nitric Oxide, Folate and Radicals in the progressively damaged endothelium[J]. Clin Chem Lab Med 2003,41(11):1444-1454
[33]Seon-Jin Lee, Ki-Mo Kim. Nitric Oxide Inhibition of Homocysteine-induced Human Endothelial Cell Apoptosis by Down-regulation of p53-dependent Noxa Expression through the Formation of S-Nitrosohomocysteine[J]. The Journal of Biological Chemistry,2005,15,5781-5788
[34]Markus C, Stiihlinger, Philip S. Tsao,et al. Homocysteine impairs the Nitric Oxide Synthase Pathway[J]. Circulation,2001,104:2569-2575
[35]Welch GN, Upchurch GR Jr, Farivar RS, et al. Homocysteine-induced nitric oxide production in vascular smooth-muscle cells by NF-kappa B-dependent transcriptional activation of Nos2[J]. Proc Assoc Am Physicians,1998, 110(1):22-31
[36]马向红,黄体刚,周丽娟.同型半胱氨酸对大鼠内皮细胞分泌一氧化氮、血管紧张素Ⅱ、内皮素的影响[J].中国心血管杂志,1998,3(5)：344-348
[37]Xiaohui Zhang, Hong Li, Haoli Jin, et al. Effects of homocysteine on endothelial nitric oxide production[J]. AJP-Renal Physiol,2000,279,671-678
[38]Rodgers G M,Kane WH. Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator[J]. JClinInvest,1986,77(6):1909-1916
[39]Undas A, Williams EB, Butenas S,et al. Homocysteine inhibits inactivation of factor Va by activated protein C[J].Biol Chem,2001,276(6):4389-4397
[40]Leoncini G, Bruzzese D, Signorello M G. Activation of p38MAPK in ase /cPLA2 pathway in homocysteine-treated plateletes[J]. JThrombHasemost,2006, 4(1):209-216
[40]陈景开,周辽军,赵秋良.高同型半胱氨酸血症与LDL氧化修饰及动脉粥样硬化的关系[J].解放军医学杂志,2001,26(5)：327-329
[41]Hopkins PN, Wull, Hunt DC, et al. Lipoprotein (a) interactions with lipid and nonlipid risk factors in early familial coronary artery disease[J]. Arterioscler Thomb VascuBiol,1997,17(11):2783-2792
[42]Young PB,Kennedy S, Molloy AM,et al. Lipid peroxidation induced in vivo by hyperhomocysteinemia in pigs[J].Atherosclerosis,1997,129(1):67-71
[43]Tsai J C, Wang H, Perrella M A, et al. Induction of cyclin A gene expression by homocysteine in vascular smooth muscle cells[J]. JClinInvest,1996,97(1):146-153
[44]Dalton ML, Gadson PF, Wrenn PW, et al. Homocysteine signal cascade: production of phospholipids, activation of protein kinase C, and the induction of c-fos and c-myb in smoothmuscle cells[J]. FASEBJ,1997,11(8):703-711
[45]Baumbach GL, Sigmund CD, Bottiglieri T,et al. Structure of cerebral arterioles in cystathionine beta-synthase-deficientmice[J]. CircRes,2002,91(10):931-937
[46]Postea O, Krotz F, Henger A, et al. Stereospecific and redox-sensitive increase in monocyte adhesion to endothelial cells by homocysteine [J]. Arterioscler Thromb Vase Biol,2006,26(3):508-513
[47]Glushchenko AV, Jacobsen DW. Molecular targeting of proteins by L-homocysteine mechanistic implications for vascular disease[J]. Antioxid Redox Signal,2007,9(11):1883-1898
[48]Jakubowski, Hieronim. Protein homocysteinylation:possible mechanism underlying pathological consequences of elevated homocysteine levels [J]. FASEB J,1999(13):2277-2283
[49]Kostner G M, Steinmeta A. Standardization of Lp(a) measurement[J]. Clin Genet,1997,52(2):393-397
[50]Marcovina S M, Albers J J, Scanu A M, et al. Use of a reference maerial proposed by the International Federation of Clinical Chemistry and Laboratory Medicine to evaluate analytical methods for the determination of plasma lipoprotein(a)[J]. Clin Chem,2000,46(12): 1956-1967
[51]Frantzen F, Faaren A L, Alfheim I, et al. Enzyme conversion immunoassay for determining total homocysteine in plasma or serum[J]. Clin Chem, 1998,44(2): 311-316
[52]Amores-Sanchez M I, Medina M A. Method for the determination of plasma total homocysteine [J]. Clin Chem Lad Med,2000,38(3);199-204
[53]Guo H, Lee JD, Ueda ,et al. Hyperhomocysteinaemia &folic and supplementation in patient s with high risk of coronary artery disease[J ] . Indian J Med Res ,2004,119 (1): 33-37.
[54]Lobo A, Naso A, Arheart K, et al. Reduction of homocysteine levels in coronary artery disease by low- dose folic acid combined with vitamins B6 and B12 [ J] . AM J Cardiol 1999,83(6):821-825.
[55]Anderson JL, J ensen KR, Caelquist J , et al. Effect of folic acidfortification of food on homocysteine - related mortality[J]. Am J Med,2004,l 16 (2):158-164
[56]Narin F, Narin N, Akcakus M, et al. The effect of folic acid, vitamin B6 and vitamin B12 no the homocysteine levels in rabbit s fed by methionine - enriched diets[J ]. Tohoku Journal of Experimental Med.icine, 2002,198 (2): 99-105.
[57]Steenge GR, Verhoef P, Katan MB, et al. Betaine supplementation lowers plasma homocysteine in healthy men and women[J ]. J Nut r,2003,133(5): 1291-1295.
[58]Sakamoto A, Sakura N. Limited effectiveness of betaine therapy for cystathionine beta synthase deficiency [J]. Pediatr Int, 2003,45:333-338.
[59]石彦荣,唐朝.牛磺酸的跨细胞膜转运[J].国外医学生理、病理科学与临床分册,2001,61：553-456.
[60]Chang L, Xu J, Yu F, et al. Taurine protected myocardial mitiochondria injury induced by hyperhomocysteinemia in rats[J]. Amino Acids, 2004,27:37-48.
[61]Zhao W, Zhang J, Lu Y, et al. The vasorelaxnt effect of H2S as a novel endogenous gaseous K(ATP) channel opener[J]. EMBO J, 2001,20:6008-6016.