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Endothelial cell dysfunction in a model of oxidative stress.

Liming Jin, Gamal Abou-Mohamed, Ruth B Caldwell, William R Caldwell

Med Sci Monit 2001; 7(4): BR585-591

ID: 421099

BACKGROUND: We have investigated the role of L-arginine in hyperhomocysteinemia(HHCY). L-arginine is the substrate required for NO production by endothelial NOS (eNOS). When L-arginineis limited, NOS acts principally upon O2 to form superoxide (O2.-). Because HHCY causes formation ofreactive oxygen species and reduced endothelial-dependent vasodilation, we hypothesized that HHCY decreasesNO formation by limiting the cellular supply of L-arginine.MATERIAL AND METHODS: Studies with culturedbovine aortic endothelial cells (ECs) determined effects of HCY on transport of [3H] L-arginine. Effectson L-arginine transporter protein CAT-1 and eNOS protein were assessed by immunoblotting. Peroxynitriteformation was evaluated by an immunoassay for nitrotyrosine levels. eNOS activity in forming NO was determinedby assay for 3H-L-arginine to 3H-citrulline conversion.RESULTS: HCY had a depressive effect on argininetransport in ECs. HCY treatment for a 24 hr period decreased arginine uptake by 27%. HCY treatment for24 hr significantly reduced cellular levels of the CAT-1 arginine transporter protein ( approximately30%) and increased nitrotyrosine formation, whereas levels of eNOS protein and basal NOS activity werenot altered. Nevertheless, total NO production as indicated by citrulline conversion was significantlydecreased. Treatment with the antioxidant N-acetylcysteine reversed the HCY effect on arginine transport,suggesting that transporter oxidation may contribute to the endothelial dysfunction.CONCLUSIONS: Theassociation of HCY-induced decreases in NO formation with decreases in function and expression of thearginine transporter in the absence of alterations in eNOS expression or activity suggests a primaryrole for arginine transport alterations in HHCY. The action of HCY to reduce arginine uptake may accentuateendothelial dysfunction due to generation of O2.- and peroxynitrite formation, which may cause furtheroxidative injury.

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