Oxidative stress and platelet activation in homozygous homocystinuria

Abstract

Background - Severe hyperhomocysteinemia due to cystathionine β-synthase deficiency (CβSD) is associated with early atherothrombotic vascular disease. Homocysteine may exert its effects by promoting oxidative damage. In the present study, we investigated whether in vivo formation of 8-iso-prostaglandin (PG) F2α, a platelet-active product of arachidonic acid peroxidation, is enhanced in CβSD and whether it correlates with in vivo platelet activation, as reflected by thromboxane (TX) metabolite excretion. Methods and Results - Urine and blood samples were obtained from patients with homozygous CβSD (n=13) and age-matched healthy subjects. Urinary 8-iso-PGF2α excretion was significantly higher in CβSD patients than in control subjects (640±384 versus 213±43 pg/mg creatinine; P=0.0015) and correlated with plasma homocysteine (ρ=0.398, P=0.0076). Similarly, urinary 11-dehydro-TXB2 excretion was enhanced in CβSD (1166±415 versus 324±72 pg/mg creatinine; P=0.0015) and correlated with urinary 8-iso-PGF2α (p=0.362, P=0.0153). Vitamin E supplementation (600 mg/d for 2 weeks) was associated with a statistically significant increase in its plasma levels (from 16.6±4.6 - to 40.4±8.7 μmol/L, P=0.0002) and with reductions in 8-iso-PGF2α (from 790±159 to 559±111 pg/mg creatinine, P=0.018) and 11-dehydro-TXB2 (from 1273±383 to 913±336 pg/mg creatinine, P=0.028). A statistically significant inverse correlation was found between urinary 8-iso-PGF2α and plasma vitamin E levels (ρ=-0.745, P=0.0135). Conclusions - The results of the present study suggest that enhanced peroxidation of arachidonic acid to form bioactive F2-isoprostanes may represent an important mechanism linking hyperhomocysteinemia and platelet activation in CβSD patients. Moreover, they provide a rationale for dose-finding studies of vitamin E supplementation in this setting.