Davì G, Di Minno G, Coppola A, Andria G, Cerbone A M, Madonna P, Tufano A, Falco A, Marchesani P, Ciabattoni G, Patrono C
Center of Excellence on Aging, Department of Biomedical Sciences, University of Chieti G. D'Annunzio, Chieti, Italy.
Circulation. 2001 Sep 4;104(10):1124-8. doi: 10.1161/hc3501.095287.
Severe hyperhomocysteinemia due to cystathionine beta-synthase deficiency (CbetaSD) 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) F(2alpha), a platelet-active product of arachidonic acid peroxidation, is enhanced in CbetaSD and whether it correlates with in vivo platelet activation, as reflected by thromboxane (TX) metabolite excretion.
Urine and blood samples were obtained from patients with homozygous CbetaSD (n=13) and age-matched healthy subjects. Urinary 8-iso-PGF(2alpha) excretion was significantly higher in CbetaSD patients than in control subjects (640+/-384 versus 213+/-43 pg/mg creatinine; P=0.0015) and correlated with plasma homocysteine (rho=0.398, P=0.0076). Similarly, urinary 11-dehydro-TXB(2) excretion was enhanced in CbetaSD (1166+/-415 versus 324+/-72 pg/mg creatinine; P=0.0015) and correlated with urinary 8-iso-PGF(2alpha) (rho=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 micromol/L, P=0.0002) and with reductions in 8-iso-PGF(2alpha) (from 790+/-159 to 559+/-111 pg/mg creatinine, P=0.018) and 11-dehydro-TXB(2) (from 1273+/-383 to 913+/-336 pg/mg creatinine, P=0.028). A statistically significant inverse correlation was found between urinary 8-iso-PGF(2alpha) and plasma vitamin E levels (rho=-0.745, P=0.0135).
The results of the present study suggest that enhanced peroxidation of arachidonic acid to form bioactive F(2)-isoprostanes may represent an important mechanism linking hyperhomocysteinemia and platelet activation in CbetaSD patients. Moreover, they provide a rationale for dose-finding studies of vitamin E supplementation in this setting.
由于胱硫醚β合酶缺乏（CβSD）导致的严重高同型半胱氨酸血症与早期动脉粥样硬化血栓形成性血管疾病相关。同型半胱氨酸可能通过促进氧化损伤发挥作用。在本研究中，我们调查了在CβSD患者中，花生四烯酸过氧化的血小板活性产物8-异前列腺素（PG）F2α的体内形成是否增强，以及它是否与体内血小板活化相关，这可通过血栓素（TX）代谢产物排泄来反映。
从纯合CβSD患者（n = 13）和年龄匹配的健康受试者中获取尿液和血液样本。CβSD患者的尿8-异PGF2α排泄显著高于对照组（640±384对213±43 pg/mg肌酐；P = 0.0015），且与血浆同型半胱氨酸相关（ρ = 0.398，P = 0.0076）。同样，CβSD患者的尿11-脱氢-TXB2排泄也增加（1166±415对324±72 pg/mg肌酐；P = 0.0015），并与尿8-异PGF2α相关（ρ = 0.362，P = 0.0153）。补充维生素E（600 mg/d，持续2周）使其血浆水平有统计学显著升高（从16.6±4.6至40.4±8.7 μmol/L，P = 0.0002），同时8-异PGF2α（从790±159至559±111 pg/mg肌酐，P = 0.018）和11-脱氢-TXB2（从1273±383至913±336 pg/mg肌酐，P = 0.028）降低。尿8-异PGF2α与血浆维生素E水平之间存在统计学显著的负相关（ρ = -0.745，P = 0.0135）。
本研究结果表明，花生四烯酸过氧化增强以形成生物活性F2-异前列腺素可能是CβSD患者高同型半胱氨酸血症与血小板活化之间联系的重要机制。此外，它们为在这种情况下进行维生素E补充剂量探索研究提供了理论依据。
