Redox Status and Protein Binding of Plasma Homocysteine and Other Aminothiols in Patients With Early-Onset Peripheral Vascular Disease

Abstract

Abstract Elevated total homocysteine (Hcy) in plasma is an independent risk factor for early-onset vascular disease in the coronary, cerebral, and peripheral arteries. Different forms of Hcy, and their relation to other aminothiols in plasma, have not been investigated in patients with vascular disease. We therefore investigated 65 patients (35 men and 30 women) operated on for peripheral arterial disease at <50 years of age and 65 age- and sex-matched control subjects. Total, reduced, oxidized, and protein-bound Hcy, cysteine (Cys), and cysteinylglycine (CysGly) were measured 0 to 11 years (mean, 6 years) postoperatively, in the fasting state, and after a standard methionine loading dose that caused a transient increase in reduced, oxidized, and protein-bound Hcy. All forms of Hcy and Cys, except reduced Cys, were higher in fasting patients than fasting control subjects. A similar difference between the groups was observed after methionine loading. The levels of most Hcy forms both during fasting and after methionine loading were related to smoking, but multivariate analysis showed that the difference between patients and control subjects could not be explained by smoking alone. Notably, reduced Cys and the reduced/total ratio for Cys were significantly higher in control subjects than in patients, both during fasting and after methionine loading. In both groups, the redox status and protein binding of the various aminothiols in plasma were interactive, as demonstrated by positive correlations between their reduced/total ratios and by a decrease in protein-bound Cys when protein-bound Hcy was elevated during methionine loading. Serum folate and to a lesser degree serum cobalamin and vitamin B 6 were predictors of oxidized and protein-bound Hcy in some patients and control subject subgroups. Thus, reduced, oxidized, and protein-bound Hcy are elevated and reduced Cys is decreased in patients with peripheral arterial disease. Reduced Hcy acts as a pro-oxidant in vitro and is a possible atherogenic agent, whereas reduced Cys may be a protective agent as a part of the antioxidant defense system. The protein binding and redox status of different plasma aminothiols are interactive in a way suggesting ongoing redox cycling and disulfide exchange reactions. Thus, Hcy is one component in a complex system.