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

Alfredo Dragani; Angela Falco; Francesca Santilli; Stefania Basili; Giancarlo Rolandi; Loredana Cerasa; Stefano Lattanzio; Giovanni Ciabattoni; Carlo Patrono; Giovanni Davì

doi:10.1160/TH11-12-0899

Thrombosis and Haemostasis, Table of Contents

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

¹Departments 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

³Department of Medicine, “La Sapienza”, University of Rome, Rome, Italy

,

Giancarlo Rolandi

¹Departments 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

⁴Department 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

› Author Affiliations

Abstract

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)F_2α 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-PGF_2α 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-PGF_2α (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-PGF_2α 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-PGF_2α 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

Full Text

References

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