PDF herunterladen
Thromb Haemost 2012; 108(03): 533-542
DOI: 10.1160/TH11-12-0899
Platelets and Blood Cells
Schattauer GmbH

Oxidative stress and platelet activation in subjects with moderate hyperhomocysteinaemia due to MTHFR 677 C→T polymorphism

Alfredo Dragani
1   Departments of Haematology and Laboratory Medicine, Civil Hospital Pescara, Italy
,
Angela Falco
2   “G. d’Annunzio” University Foundation and Department of Drug Sciences, University of Chieti “G. d’Annunzio” Schools of Medicine and Pharmacy, Chieti, Italy
,
Francesca Santilli
2   “G. d’Annunzio” University Foundation and Department of Drug Sciences, University of Chieti “G. d’Annunzio” Schools of Medicine and Pharmacy, Chieti, Italy
,
Stefania Basili
3   Department of Medicine, “La Sapienza”, University of Rome, Rome, Italy
,
Giancarlo Rolandi
1   Departments of Haematology and Laboratory Medicine, Civil Hospital Pescara, Italy
,
Loredana Cerasa
2   “G. d’Annunzio” University Foundation and Department of Drug Sciences, University of Chieti “G. d’Annunzio” Schools of Medicine and Pharmacy, Chieti, Italy
,
Stefano Lattanzio
2   “G. d’Annunzio” University Foundation and Department of Drug Sciences, University of Chieti “G. d’Annunzio” Schools of Medicine and Pharmacy, Chieti, Italy
,
Giovanni Ciabattoni
2   “G. d’Annunzio” University Foundation and Department of Drug Sciences, University of Chieti “G. d’Annunzio” Schools of Medicine and Pharmacy, Chieti, Italy
,
Carlo Patrono
4   Department of Pharmacology, Catholic University School of Medicine, Rome, Italy
,
Giovanni Davì
2   “G. d’Annunzio” University Foundation and Department of Drug Sciences, University of Chieti “G. d’Annunzio” Schools of Medicine and Pharmacy, Chieti, Italy
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received: 28. Dezember 2011

Accepted after major revision: 12. Juni 2012

Publikationsdatum:
25. November 2017 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Summary

The methylenetetrahydrofolate reductase (MTHFR) 677 C→T polymorphism may be associated with elevated total homocysteine (tHcy) levels, an independent risk factor for cardiovascular disease. It was the study objective to evaluate in vivo lipid peroxidation and platelet activation in carriers of the MTHFR 677 C→T polymorphism and in non-carriers, in relation to tHcy and folate levels. A cross-sectional comparison of urinary 8-iso-prostaglandin (PG)F2α and 11-dehydro-thromboxane (TX)B2 (markers of in vivo lipid peroxidation and platelet activation, respectively) was performed in 100 carriers and 100 non-carriers of the polymorphism. A methionine-loading test and folic acid supplementation were performed to investigate the causal relationship of the observed associations. Urinary 8-iso-PGF2α and 11-dehydro-TXB2 were higher in carriers with hyperhomocysteinaemia than in those without hyperhomocysteinaemia (p<0.0001). Hyperhomocysteinaemic carriers had lower folate levels (p=0.0006), higher urinary 8-iso-PGF2α (p<0.0001) and 11-dehydro-TXB2 (p<0.0001) than hyperhomocysteinaemic non-carriers. On multiple regression analysis, high tHcy (p<0.0001), low folate (p<0.04) and MTHFR 677 C→T polymorphism (p<0.001) independently predicted high rates of 8-iso-PGF2α excretion. Methionine loading increased plasma tHcy (p=0.002), and both urinary prostanoid metabolites (p=0.002). Folic acid supplementation was associated with decreased urinary 8-iso-PGF2α and 11-dehydro-TXB2 excretion (p<0.0003) in the hyperhomocysteinaemic group, but not in the control group, with substantial inter-individual variability related to baseline tHcy level and the extent of its reduction. In conclusion, hyperhomocysteinaemia due to the MTHFR 677 C→T polymorphism is associated with enhanced in vivo lipid peroxidation and platelet activation that are reversible, at least in part, following folic acid supplementation. An integrated biomarker approach may help identifying appropriate candidates for effective folate supplementation.

Keywords

Hyperhomocysteinaemia - MTHFR 677 C→T polymorphism - oxidative stress - platelet activation - folate supplementation

 

  • References

  • 1 Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med 1998; 338: 1042-1050.
    CrossrefPubMedGoogle Scholar
  • 2 Durand P. et al. Impaired homocysteine metabolism and atherothrombotic disease. Lab Invest 2001; 81: 645-672.
    CrossrefPubMedGoogle Scholar
  • 3 Wald DS. et al. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. Br Med J 2002; 325: 1202-1208.
    CrossrefPubMedGoogle Scholar
  • 4 The Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. J Am Med Assoc. 2002 288. 2015-2022.
    PubMedGoogle Scholar
  • 5 Klerk M. et al. MTHFR Studies Collaboration Group. MTHFR 677C→T polymorphism and risk of coronary heart disease: a meta-analysis. J Am Med Assoc 2002; 288: 2023-2031.
    CrossrefPubMedGoogle Scholar
  • 6 Zee RY. et al. Homocysteine, 5,10-methylenetetrahydrofolate reductase 677C>T polymorphism, nutrient intake, and incident cardiovascular disease in 24,968 initially healthy women. Clin Chem 2007; 53: 845-851.
    CrossrefPubMedGoogle Scholar
  • 7 Lewis SJ. et al. Meta-analysis of MTHFR 677C->T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate?. Br Med J 2005; 331: 1053.
    CrossrefPubMedGoogle Scholar
  • 8 Malinow MR. et al. The effects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and methylenetetrahydrofolate reductase genotypes. Arterioscler Thromb Vasc Biol 1997; 17: 1157-1162.
    CrossrefPubMedGoogle Scholar
  • 9 Holmes M V. et al. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials. Lancet 2011; 378: 584-594.
    CrossrefPubMedGoogle Scholar
  • 10 Liem A. et al. Secondary prevention with folic acid: effects on clinical outcomes. J Am Coll Cardiol 2003; 41: 2105-2113.
    CrossrefPubMedGoogle Scholar
  • 11 Bonaa KH. et al. NORVIT Trial Investigators. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006; 354: 1578-1588.
    CrossrefPubMedGoogle Scholar
  • 12 Lonn E. et al. Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006; 354: 1567-1577.
    PubMedGoogle Scholar
  • 13 Albert CM. et al. Effect of Folic Acid and B Vitamins on Risk of Cardiovascular Events and Total Mortality Among Women at High Risk for Cardiovascular Disease: A Randomized Trial. J Am Med Assoc 2008; 299: 2027-2036.
    CrossrefPubMedGoogle Scholar
  • 14 SEARCH Collaborative Group. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. J Am Med Assoc. 2010 303. 2486-2494.
    PubMedGoogle Scholar
  • 15 Clarke R. et al. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: Meta-analysis of 8 randomized trials involving 37 485 individuals. Arch Intern Med 2010; 170: 1622-1631.
    CrossrefPubMedGoogle Scholar
  • 16 Clarke R. et al. Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias. PLoS Med 2012; 09: e1001177.
    CrossrefPubMedGoogle Scholar
  • 17 Loscalzo J. The oxidant stress of hyperhomocyst(e)inemia. J Clin Invest 2006; 98: 5-7.
    PubMedGoogle Scholar
  • 18 Davì G. et al. Oxidative stress and platelet activation in homozygous homocystinuria. Circulation 2001; 104: 1124-1128.
    CrossrefPubMedGoogle Scholar
  • 19 Papatheodorou L, Weiss N. Vascular oxidant stress and inflammation in hyperhomocysteinemia. Antiox Redox Signal 2007; 09: 1941-1958.
    CrossrefPubMedGoogle Scholar
  • 20 Podrez EA. et al. Platelet CD36 links hyperlipidemia, oxidant stress and a prothrombotic phenotype. Nat Med 2007; 13: 1086-1095.
    CrossrefPubMedGoogle Scholar
  • 21 Patrono C, FitzGerald GA. Isoprostanes: potential markers of oxidant stress in atherothrombotic disease. Arterioscler Thromb Vasc Biol 1997; 17: 2309-2315.
    CrossrefPubMedGoogle Scholar
  • 22 Milne GL. et al. Human biochemistry of the isoprostane pathway. J Biol Chem 2008; 283: 15533-15537.
    CrossrefPubMedGoogle Scholar
  • 23 Braunwald E. Biomarkers in heart failure. N Engl J Med 2008; 358: 2148-2159.
    CrossrefPubMedGoogle Scholar
  • 24 Davì G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007; 357: 2482-2494.
    CrossrefPubMedGoogle Scholar
  • 25 Ciabattoni G. et al. Fractional conversion of thromboxane B2 to urinary 11-dehydro-thromboxane B2 in man. Biochim Biophys Acta 1989; 992: 66-70.
    CrossrefPubMedGoogle Scholar
  • 26 Frosst P. et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111-113.
    CrossrefPubMedGoogle Scholar
  • 27 Margaglione M. et al. The methylenetetrahydrofolate reductase TT677 genotype is associated with venous thrombosis independently of the coexistence of the FV Leiden and the prothrombin A20210 mutation. Thromb Haemost 1998; 79: 907-911.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 28 Shipchandler MT, Moore EG. Rapid, fully automatic measurement of plasma homocyst(e)ine with the Abbott IMx analyzer. Clin Chem 1995; 41: 991-994.
    PubMedGoogle Scholar
  • 29 Zighetti ML. et al. Determination of total homocysteine in plasma: comparison of the Abbott IMx immunoassay with high performance liquid chromatography. Haematologica 2002; 87: 89-94.
    PubMedGoogle Scholar
  • 30 Wang Z. et al. Immunological characterization of urinary 8-epi-prostaglandin F?excretion in man. J Pharmacol Exp Ther 1995; 275: 94-100.
    PubMedGoogle Scholar
  • 31 Ciabattoni G. et al. Radioimmunoassay of 11-dehydro-TXB2 in human plasma and urine. Biochim Biophys Acta 1987; 918: 293-297.
    CrossrefPubMedGoogle Scholar
  • 32 Martinelli I. et al. Hyperhomocysteinemia in cerebral vein thrombosis. Blood 2003; 102: 1363-1366.
    CrossrefPubMedGoogle Scholar
  • 33 Cattaneo M. Hyperhomocysteinemia, atherosclerosis and thrombosis. Thromb Haemost 1999; 81: 165-176.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 34 Voutilainen S. et al. Enhanced in vivo lipid peroxidation at elevated plasma total homocysteine levels. Arterioscler Thromb Vasc Biol 1999; 19: 1263-1266.
    CrossrefPubMedGoogle Scholar
  • 35 Audoly LP. et al. Cardiovascular responses to the isoprostanes iPF(2alpha)-III and iPE(2)-III are mediated via the thromboxane A(2) receptor in vivo. Circulation 2000; 101: 2833-2840.
    CrossrefPubMedGoogle Scholar
  • 36 Minuz P. et al. The F2-isoprostane 8-epiprostaglandin F2alpha increases platelet adhesion and reduces the antiadhesive and antiaggregatory effects of NO. Arterioscler Thromb Vasc Biol 1998; 18: 1248-1256.
    CrossrefPubMedGoogle Scholar
  • 37 Pignatelli P. et al. Inherited human gp91phox deficiency is associated with impaired isoprostane formation and platelet dysfunction. Arterioscler Thromb Vasc Biol 2011; 31: 423-434.
    CrossrefPubMedGoogle Scholar
  • 38 Cronin S. et al. Dose-related association of MTHFR 677T allele with risk of ischemic stroke. Evidence from a cumulative meta-analysis. Stroke 2005; 36: 1581-1587.
    CrossrefPubMedGoogle Scholar
  • 39 Shirodaria C. et al. Global improvement of vascular function and redox state with low-dose folic acid: implications for folate therapy in patients with coronary artery disease. Circulation 2007; 115: 2262-2270.
    CrossrefPubMedGoogle Scholar
  • 40 Schnyder G. et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001; 345: 1593-1600.
    CrossrefPubMedGoogle Scholar
  • 41 Loscalzo J. Homocysteine trials – Clear outcomes for complex reasons. N Engl J Med 2006; 354: 1629-1632.
    CrossrefPubMedGoogle Scholar
  • 42 Wang X. et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet 2007; 369: 1876-1882.
    CrossrefPubMedGoogle Scholar
  • 43 Bazzano LA. et al. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. J Am Med Assoc 2006; 296: 2720-2726.
    CrossrefPubMedGoogle Scholar