title: [Hyperhomocysteinemia: an independent risk factor or a simple marker of vascular disease?. 1. Basic data].
abstract: Recent epidemiological studies have suggested that hyperhomocysteinemia is associated with increased risk of vascular disease. Homocysteine is a sulphur-containing amino acid whose metabolism stands at the intersection of two pathways: remethylation to methionine, which requires folate and vitamin B12 (or betaine in an alternative reaction); and transsulfuration to cystathionine which requires vitamin B6. The two pathways are coordinated by S-adenosylmethionine which acts as an allosteric inhibitor of the methylenetetrahydrofolate reductase (MTHFR) and as an activator of cystathionine beta-synthase (CBS). Hyperhomocysteinemia arises from disrupted homocysteine metabolism. Severe hyperhomocysteinemia is due to rare genetic defects resulting in deficiencies in CBS, MTHFR, or in enzymes involved in methyl cobalamine synthesis and homocysteine methylation. Mild hyperhomocysteinemia seen in fasting condition is due to mild impairment in the methylation pathway (i.e. folate or B12 deficiencies or MTHFR thermolability). Post-methionine-load hyperhomocysteinaemia may be due to heterozygous cystathionine-beta-synthase defect or B6 deficiency. Patients with homocystinuria and severe hyperhomocysteinemia develop arterial thrombotic events, venous thromboembolism, and more seldom premature arteriosclerosis. Experimental evidence suggests that an increased concentration of homocysteine may result in vascular changes through several mechanisms. High levels of homocysteine induce sustained injury of arterial endothelial cells, proliferation of arterial smooth muscle cells and enhance expression/activity of key participants in vascular inflammation, atherogenesis, and vulnerability of the established atherosclerotic plaque. These effects are supposed to be mediated through its oxidation and the concomitant production of reactive oxygen species. Other effects of homocysteine include: impaired generation and decreased bioavailability of endothelium-derived relaxing factor/nitric oxide; interference with many transcription factors and signal transduction; oxidation of low-density lipoproteins; lowering of endothelium-dependent vasodilatation. In fact, the effect of elevated homocysteine appears multifactorial affecting both the vascular wall structure and the blood coagulation system.
authors.affiliation: Laboratoire de physiologie, UFR de médecine, BP 87900, 21079 cedex, Dijon, France. jean-claude.guilland@chu-dijon.fr <jean-claude.guilland@chu-dijon.fr>
authors.forename: J-C
authors.initials: JC
authors.lastname: Guilland
authors.forename: A
authors.initials: A
authors.lastname: Favier
authors.forename: G
authors.initials: G
authors.lastname: Potier de Courcy
authors.forename: P
authors.initials: P
authors.lastname: Galan
authors.forename: S
authors.initials: S
authors.lastname: Hercberg
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000097:blood / Q000453:epidemiology; D015415:Biomarkers; D003541:Cystathionine beta-Synthase / Q000172:deficiency / Q000235:genetics; D005494:Folic Acid Deficiency / Q000150:complications; D020022:Genetic Predisposition to Disease; D006710:Homocysteine / Q000378:metabolism; D006712:Homocystinuria / Q000150:complications / Q000235:genetics; D006801:Humans; D020138:Hyperhomocysteinemia / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics; D008715:Methionine / Q000378:metabolism; D008745:Methylation; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008954:Models, Biological; D009569:Nitric Oxide / Q000172:deficiency; D018384:Oxidative Stress; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012307:Risk Factors; D012436:S-Adenosylmethionine / Q000378:metabolism; D015398:Signal Transduction; D019851:Thrombophilia / Q000097:blood / Q000453:epidemiology / Q000209:etiology; D014652:Vascular Diseases / Q000097:blood / Q000453:epidemiology*; D014664:Vasodilation; D026681:Vitamin B 6 Deficiency / Q000150:complications
chemical_list: D015415:Biomarkers; D006710:Homocysteine; D009569:Nitric Oxide; D012436:S-Adenosylmethionine; D008715:Methionine; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D003541:Cystathionine beta-Synthase