ABSTRACT
Elevated levels of homocyst(e)ine may initiate arterial thrombosis and prevent natural thrombolysis by inhibiting thrombomodulin or the expression of heparin sulfate in the plasma membrane of endothelial cells constituting the vascular intima (21-26). Hydrogen peroxide released as a byproduct of homocyst(e)ine metabolism may exert oxidative stress to cause secondary injury of vascular endothelia (27-32). In vitro and animal model studies confirm that elevated levels of homocyst(e)ine promote cellular oxidative damage and may threaten endothelia, neurons, and other cell populations constituting, or dependent upon, the integrity of the intimal surface in the extracranial vessels and in the vasculature of the brain. These putative actions of homocyst(e)ine include the inhibition of nitric oxide (NO) in endothelial cells, direct cellular toxicity due to inadequate catabolism through impaired remethylation, and interactions withN-methyl-D-aspartate receptors to affect neuronal calcium conductance. As an important contributor to the pathogenesis of systemic atherosclerosis, homocyst(e)ine at peak levels may cause toxic injury to endothelial cells (33), activate platelets (34), induce procoagulant activity (35), enhance smooth muscle cell proliferation (36-38), and promote intravascular synthesis of collagen (39,40). Rats with hyperhomocyst(e)inemia that are fed a lipogenic diet become even more susceptible to intima-media hyperplasia (41). Durand et al. (42) showed that hyperhomocyst(e)inemic rats have enhanced thromboxane biosynthesis and accelerated platelet aggregation. Morita et al. (43) found excessive neo-intima formation in the wall of the carotid artery after induced endothelial injury in hyperhomocyst(e)inemic rats. In correlation with these in vitro and animal model experiments, observational studies in humans demonstrate a strong association between elevated homocyst(e)ine levels and enhanced lipid peroxidation (44) as well as increased total serum cholesterol levels (45). Hyperhomocyst(e)inemia may promote increased oxidation of LDL and cause unfavorable alterations in the level of lipoprotein (a) (46).
