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Semin Thromb Hemost 2000; Volume 26(Number 03): 281-290
DOI: 10.1055/s-2000-8472
DOI: 10.1055/s-2000-8472
Hyperhomocysteinemia, Vascular Pathology, and Endothelial Dysfunction
Further Information
Publication History
Publication Date:
31 December 2000 (online)
ABSTRACT
Hyperhomocysteinemia has been associated with premature atherothrombotic vascular disease. It is not known whether hyperhomocysteinemia induces a distinct type of vascular disease. Its interaction, if any, with traditional risk factors also remains unclear. The pathophysiological mechanisms linking hyperhomocysteinemia to vascular disease have been extensively studied in vitro and in animals. From these studies, it has been suggested that homocysteine limits the bioavailability of nitric oxide (NO), increases oxidative stress, stimulates smooth cell proliferation, and alters elastic wall properties. The relevance of these proposed mechanisms in vivo is unclear, because clinical studies have yielded controversial results with regard to the relation between plasma homocysteine levels and indices of endothelial function, such as brachial artery flow-mediated vasodilatation and plasma levels of endothelium-derived marker proteins. Up till now, there have been no controlled data on the effects of homocysteine-lowering treatment on vascular function or clinical end points. The precise mechanisms (if any) by which homocysteine mediates its adverse vascular effects are in fact unknown but may relate to impaired endothelial and smooth muscle cell function.
KEYWORD
Hyperhomocysteinemia - vascular dis- eases - endothelial function - treatment - athero-thrombosis
REFERENCES
- 1 Perry I J, Refsum H, Morris R W. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet . 1995; 346 1395-1398
- 2 Taylor L MJ, DeFrang R D, Harris E JJ, Porter J M. The association of elevated plasma homocyst(e)ine with progression of symptomatic peripheral arterial disease. J Vasc Surg . 1991; 13 128-136
- 3 Wald N J, Watt H C, Law M R. Homocysteine and ischemic heart disease: Results of a prospective study with implications regarding prevention. Arch Intern Med . 1998; 158 862-867
- 4
den Heijer M, Koster T, Blom H J.
Hyperhomocysteinemia as a risk factor for deep-vein thrombosis.
N Engl J Med .
1996;
334
759-762
MissingFormLabel
- 5 Graham I M, Daly L E, Refsum H M. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA . 1997; 277 1775-1781
- 6 Evans R W, Shaten B J, Hempel J D, Cutler J A, Kuller L H. Homocyst(e)ine and risk of cardiovascular disease in the Multiple Risk Factor Intervention Trial. Arterioscler Thromb Vasc Biol . 1997; 17 1947-1953
- 7 Wang H, Yoshizumi M, Lai K. Inhibition of growth and p21ras methylation in vascular endothelial cells by homocysteine but not cysteine. J Biol Chem . 1997; 272 25380-25385
- 8 Perna A F, Ingrosso D, Galletti P, Zappia V, De Santo N G. Membrane protein damage and methylation reactions in chronic renal failure. Kidney Int . 1996; 50 358-366
- 9
McCully K S.
Vascular pathology of homocysteinemia: Implications for the pathogenesis of arteriosclerosis.
Am J Pathol .
1969;
56
111-128
MissingFormLabel
- 10 Gibson J B, Carson N AJ, Neill D W. Pathological findings in homocystinuria. J Clin Pathol . 1964; 17 427-437
- 11 Harker L A, Ross R, Slichter S J, Scott C R. Homocystine-induced arteriosclerosis. The role of endothelial cell injury and platelet response in its genesis. J Clin Invest . 1976; 58 731-741
- 12 McCully K S, Ragsdale B D. Production of arteriosclerosis by homocysteinemia. Am J Pathol . 1970; 61 1-11
- 13 Reddy G S, Wilcken D E. Experimental homocysteinemia in pigs: Comparison with studies in sixteen homocystinuric patients. Metabolism . 1982; 31 778-783
- 14 Dudman N P, Wilcken D E. Homocysteine thiolactone and experimental homocysteinemia. Biochem Med . 1982; 27 244-253
- 15 Matthias D, Becker C H, Riezler R, Kindling P H. Homocysteine induced arteriosclerosis-like alterations of the aorta in normotensive and hypertensive rats following application of high doses of methionine. Atherosclerosis . 1996; 122 201-216
- 16 McCully K S, Wilson R B. Homocysteine theory of arteriosclerosis. Atherosclerosis . 1975; 22 215-227
- 17 Rolland P H, Friggi A, Barlatier A. Hyperhomocysteinemia-induced vascular damage in the minipig. Captopril-hydrochlorothiazide combination prevents elastic alterations. Circulation . 1995; 91 1161-1174
- 18 Ubbink J B, Vermaak W J, Bennett J M. The prevalence of homocysteinemia and hypercholesterolemia in angiographically defined coronary heart disease. Klin Wochenschr . 1991; 69 527-534
- 19 von Eckardstein A, Malinow M R, Upson B. Effects of age, lipoproteins, and hemostatic parameters on the role of homocyst(e)inemia as a cardiovascular risk factor in men. Arterioscler Thromb . 1994; 14 460-464
- 20 Nygard O, Nordrehaug J E, Refsum H. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med . 1997; 337 230-236
- 21 Verhoef P, Kok F J, Kruyssen D A. Plasma total homocysteine, B vitamins, and risk of coronary atherosclerosis. Arterioscler Thromb Vasc Biol . 1997; 17 989-995
- 22 Montalescot G, Ankri A, Chadefaux-Vekemans B. Plasma homocysteine and the extent of atherosclerosis in patients with coronary artery disease. Int J Cardiol . 1997; 60 295-300
- 23 Yoo J H, Chung C S, Kang S S. Relation of plasma homocyst(e)ine to cerebral infarction and cerebral atherosclerosis. Stroke . 1998; 29 2478-2483
- 24 Fassbender K, Mielke O, Bertsch T. Homocysteine in cerebral macroangiopathy and microangiopathy. Lancet . 1999; 353 1586-1587
- 25 van den Berg M, Stehouwer C D, Bierdrager E, Rauwerda J A. Plasma homocysteine and severity of atherosclerosis in young patients with lower-limb atherosclerotic disease. Arterioscler Thromb Vasc Biol . 1996; 16 165-171
- 26 Selhub J, Jacques P F, Bostom A G. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med . 1995; 332 286-291
- 27 de Jong S C, Stehouwer C D, Mackaay A J. High prevalence of hyperhomocysteinemia and asymptomatic vascular disease in siblings of young patients with vascular disease and hyperhomocysteinemia. Arterioscler Thromb Vasc Biol . 1997; 17 2655-2662
- 28 Clarke R, Fitzgerald D, O'Brien C. Hyperhomocysteinaemia: A risk factor for extracranial carotid artery atherosclerosis. Ir J Med Sci . 1992; 161 61-65
- 29 Malinow M R, Nieto F J, Szklo M, Chambless L E, Bond G. Carotid artery intimal-medial wall thickening and plasma homocyst(e)ine in asymptomatic adults. The Atherosclerosis Risk in Communities Study. Circulation . 1993; 87 1107-1113
- 30 Demuth K, Moatti N, Hanon O. Opposite effects of plasma homocysteine and the methylenetetrahydrofolate reductase C677T mutation on carotid artery geometry in asymptomatic adults. Arterioscler Thromb Vasc Biol . 1998; 18 1838-1843
- 31 Rubba P, Mercuri M, Faccenda F. Premature carotid atherosclerosis: Does it occur in both familial hypercholesterolemia and homocystinuria?. <~>Ultrasound assessment of arterial intima-media thickness and blood flow velocity. Stroke . 1994; 25 943-950
- 32 de Valk H W, van Eeden M K, Banga J D. Evaluation of the presence of premature atherosclerosis in adults with heterozygosity for cystathionine-beta-synthase deficiency. Stroke . 1996; 27 1134-1136
- 33 Tonstad S, Joakimsen O, Stensland-Bugge E. Risk factors related to carotid intima-media thickness and plaque in children with familial hypercholesterolemia and control subjects. Arterioscler Thromb Vasc Biol . 1996; 16 984-991
- 34 Smilde T J, van den Berkmortel F WPJ, Boers G HJ. Carotid and femoral artery wall thickness and stiffness in patients at risk for cardiovascular disease, with special emphasis on hyperhomocysteinemia. Arterioscler Thromb Vasc Biol . 1998; 18 1958-1963
- 35 Megnien J L, Gariepy J, Saudubray J M. Evidence of carotid artery wall hypertrophy in homozygous homocystinuria. Circulation . 1998; 98 2276-2281
- 36 Bots M L, Launer L J, Lindemans J, Hofman A, Grobbee D E. Homocysteine, atherosclerosis and prevalent cardiovascular disease in the elderly: The Rotterdam Study. J Intern Med . 1997; 242 339-347
- 37 McQuillan B M, Beilby J P, Nidorf M, Thompson P L, Hung J. Hyperhomocysteinemia but not the C677T mutation of methylenetetrahydrofolate reductase is an independent risk determinant of carotid wall thickening. The Perth Carotid Ultrasound Disease Assessment Study (CUDAS). Circulation . 1999; 99 2383-2388
- 38 Spence J D, Malinow M R, Barnett P A. Plasma homocyst(e)ine concentration, but not MTHFR genotype, is associated with variation in carotid plaque area. Stroke . 1999; 30 969-973
- 39 Jackson S H. The reaction of homocysteine with aldehyde: An explanation of the collagen defects in homocystinuria. Clin Chim Acta . 1973; 45 215-217
- 40 Kang A H, Trelstad R L. A collagen defect in homocystinuria. J Clin Invest . 1973; 52 2571-2578
- 41 Tawakol A, Omland T, Gerhard M, Wu J T, Creager M A. Hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans. Circulation . 1997; 95 1119-1121
- 42 Woo K S, Chook P, Lolin Y I. Hyperhomocyst(e)inemia is a risk factor for arterial endothelial dysfunction in humans. Circulation . 1997; 96 2542-2544
- 43 Lambert J, van den Berg M, Steyn M. Familial hyperhomocysteinaemia and endothelium-dependent vasodilatation and arterial distensibility of large arteries. Cardiovasc Res . 1999; 42 743-751
- 44 van Guldener C, Lambert J, Janssen M JFM, Donker A JM, Stehouwer C DA. Endothelium-dependent vasodilatation and distensibility of large arteries in chronic haemodialysis patients. Nephrol Dial Transplant . 1997; 14-18 (14-18)
- 45 Blacher J, Demuth K, Guerin A P. Influence of biochemical alterations on arterial stiffness in patients with end-stage renal disease. Arterioscler Thromb Vasc Biol . 1998; 18 535-541
- 46 Tsai J C, Perrella M A, Yoshizumi M. Promotion of vascular smooth muscle cell growth by homocysteine: A link to atherosclerosis. Proc Natl Acad Sci USA . 1994; 91 6369-6373
- 47 Lubec B, Labudova O, Hoeger H. Homocysteine increases cyclin- dependent kinase in aortic rat tissue. Circulation . 1996; 94 2620-2625
- 48 Majors A, Ehrhart L A, Pezacka E H. Homocysteine as a risk factor for vascular disease. Enhanced collagen production and accumulation by smooth muscle cells. Arterioscler Thromb Vasc Biol . 1997; 17 2074-2081
- 49 Jawien A, Bowen-Pope D F, Lindner V, Schwartz S M, Clowes A W. Platelet- derived growth factor promotes smooth muscle migration and intimal thickening in a rat model of balloon angioplasty. J Clin Invest . 1992; 89 507-511
- 50 Jackson C L, Raines E W, Ross R, Reidy M A. Role of endogenous platelet- derived growth factor in arterial smooth muscle cell migration after balloon catheter injury. Arterioscler Thromb . 1993; 13 1218-1226
- 51 Ross R. The pathogenesis of atherosclerosis: A perspective for the 1990s. Nature . 1993; 362 801-809
- 52 Wall R T, Harlan J M, Harker L A, Striker G E. Homocysteine-induced endothelial cell injury in vitro: A model for the study of vascular injury. Thromb Res . 1980; 18 113-121
- 53 Dudman N P, Hicks C, Wang J, Wilcken D E. Human arterial endothelial cell detachment in vitro: Its promotion by homocysteine and cysteine. Atherosclerosis . 1991; 91 77-83
- 54 Starkebaum G, Harlan J M. Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Clin Invest . 1986; 77 1370-1376
- 55 Blundell G, Jones B G, Rose F A, Tudball N. Homocysteine mediated endothelial cell toxicity and its amelioration. Atherosclerosis . 1996; 122 163-172
- 56 Blann A D. Endothelial cell damage and homocysteine. Atherosclerosis . 1992; 94 89-91
- 57 Stamler J S, Osborne J A, Jaraki O. Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. J Clin Invest . 1993; 91 308-318
- 58 Jones B G, Rose F A, Tudball N. Lipid peroxidation and homocysteine induced toxicity. Atherosclerosis . 1994; 105 165-170
- 59 Heinecke J W, Kawamura M, Suzuki L, Chait A. Oxidation of low density lipoprotein by thiols: Superoxide-dependent and -independent mechanisms. J Lipid Res . 1993; 34 2051-2061
- 60 Nishio E, Watanabe Y. Homocysteine as a modulator of platelet-derived growth factor action in vascular smooth muscle cells: A possible role for hydrogen peroxide. Br J Pharmacol . 1997; 122 269-274
- 61 Upchurch G RJ, Welch G N, Fabian A J. Homocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem . 1997; 272 17012-17017
- 62 Upchurch G RJ, Welch G N, Fabian A J. Stimulation of endothelial nitric oxide production by homocyst(e)ine. Atherosclerosis . 1997; 132 177-185
- 63 Celermajer D S, Sorensen K, Ryalls M. Impaired endothelial function occurs in the systemic arteries of children with homozygous homocystinuria but not in their heterozygous parents. J Am Coll Cardiol . 1993; 22 854-858
- 64 Lentz S R, Sobey C G, Piegors D J. Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia. J Clin Invest . 1996; 98 24-29
- 65 Welch G N, Upchurch G RJ, Farivar R S. Homocysteine-induced nitric oxide production in vascular smooth-muscle cells by NF-kappa B-dependent transcriptional activation of Nos2. Proc Assoc Am Phys . 1998; 110 22-31
- 66 Ikeda U, Ikeda M, Minota S, Shimada K. Homocysteine increases nitric oxide synthesis in cytokine-stimulated vascular smooth muscle cells. Circulation . 1999; 99 1230-1235
- 67 Quere I, Hillaire-Buys D, Brunschwig C. Effects of homocysteine on acetylcholine- and adenosine-induced vasodilatation of pancreatic vascular bed in rats. Br J Pharmacol . 1997; 122 351-357
- 68 Ungvari Z, Pacher P, Rischak K, Szollar L, Koller A. Dysfunction of nitric oxide mediation in isolated rat arterioles with methionine diet-induced hyperhomocysteinemia. Arterioscler Thromb Vasc Biol . 1999; 19 1899-1904
- 69 Joannides R, Haefeli W E, Linder L. Nitric oxide is responsible for flow- dependent dilatation of human peripheral conduit arteries in vivo. Circulation . 1995; 91 1314-1319
- 70 Meredith I T, Currie K E, Anderson T J. Postischemic vasodilation in human forearm is dependent on endothelium-derived nitric oxide. Am J Physiol . 1996; 270 H1435-H1440
- 71 Anderson T J, Uehata A, Gerhard M D. Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol . 1995; 26 1235-1241
- 72 Neunteufl T, Katzenschlager R, Hassan A. Systemic endothelial dysfunction is related to the extent and severity of coronary artery disease. Atherosclerosis . 1997; 129 111-118
- 73 van Guldener C, Janssen M JFM, Lambert J. Endothelium-dependent vasodilatation is impaired in peritoneal dialysis patients. Nephrol Dial Transplant . 1998; 13 1782-1786
- 74 Joannides R, Bakkali E H, Leroy F. Altered flow-dependent vasodilatation of conduit arteries in maintenance haemodialysis. Nephrol Dial Transplant . 1997; 12 2623-2628
- 75 de Valk-de Roo G W, Stehouwer C DA, Lambert J. Plasma homocysteine is weakly correlated with plasma endothelin and von Willebrand factor, but not with endothelium-dependent vasodilatation in healthy postmenopausal women. Clin Chem . 1999; 45 1200-1205
- 76 Bellamy M F, Mcdowell I FW, Ramsey M W. Hyperhomocysteinemia after an oral methionine load acutely impairs endothelial function in healthy adults. Circulation . 1998; 98 1848-1852
- 77 Chambers J C, McGregor A, Jean-Marie J, Obeid O A, Kooner, J S. Demonstration of rapid onset vascular endothelial dysfunction after hyperhomocysteinemia-an effect reversible with vitamin C therapy. Circulation . 1999; 99 1156-1160
- 78 Usui M, Matsuoka H, Miyazaki H. Endothelial dysfunction by acute hyperhomocyst(e)inaemia: Restoration by folic acid. Clin Sci . 1999; 96 235-239
- 79 Kanani P M, Sinkey C A, Browning R L. Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocyst(e)inemia in humans. Circulation . 1999; 100 1161-1168
- 80 Verhaar M C, Wever R M, Kastelein J J. 5-Methyltetrahydrofolate, the active form of folic acid, restores endothelial function in familial hypercholesterolemia. Circulation . 1998; 97 237-241
- 81 Mansoor M A, Kristensen O, Hervig T. Low concentrations of folate in serum and erythrocytes of smokers-methionine loading decreases folate concentrations in serum of smokers and nonsmokers. Clin Chem . 1997; 43 2192-2194
- 82 Nappo F, De Rosa N, Marfella R. Impairment of endothelial functions by acute hyperhomocysteinemia and reversal by antioxidant vitamins. JAMA . 1999; 281 2113-2118
- 83 McAuley D F, Hanratty C G, McGurk C, Nugent A G, Johnston G D. Effect of methionine supplementation on endothelial function, plasma homocysteine, and lipid peroxidation. J Toxicol Clin Toxicol . 1999; 37 435-440
- 84 Lentz S R, Malinow M R, Piegors D J. Consequences of hyperhomocyst(e)inemia on vascular function in atherosclerotic monkeys. Arterioscler Thromb Vasc Biol . 1997; 17 2930-2934
- 85 van Guldener C, Janssen M JFM, Lambert J. No change in impaired endothelial function after long-term folic acid therapy of hyperhomocysteinaemia in haemodialysis patients. Nephrol Dial Transplant . 1998; 13 106-112
- 86 van Guldener C, Janssen M JFM, Lambert J. Folic acid treatment of hyperhomocysteinemia in peritoneal dialysis patients: No change in endothelial function after long-term therapy. Perit Dial Int . 1998; 18 282-289
- 87 Ambrosi P, Rolland P H, Bodard H. Effects of folate supplementation in hyperhomocysteinemic pigs. J Am Coll Cardiol . 1999; 34 274-279
- 88 Bellamy M F, McDowell I FW, Ramsey M W. Oral folate enhances endothelial function in hyperhomocysteinaemic subjects. Eur J Clin Invest . 1999; 29 659-662
- 89 Mudd S H, Skovby F, Levy H L. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet . 1985; 37 1-31
- 90 van Beynum I M, Smeitink J AM, den Heijer M, te Poele Pothoff M TWB, Blom H J. Hyperhomocysteinemia-a risk factor for ischemic stroke in children. Circulation . 1999; 99 2070-2072
- 91 Stehouwer C DA, Weijenberg M P, van den Berg M. Serum homocysteine and risk of coronary heart disease and cerebrovascular disease in elderly men-A 10-year follow-up. Arterioscler Thromb Vasc Biol . 1998; 18 1895-1901