Thyronines and probucol inhibition of human capillary endothelial cell-induced low density lipoprotein oxidation

Oxidized lipoproteins have been implicated as important factors in the pathogenicity of atherosclerosis. Thus, antioxidants play a significant role in inhibiting a critical step in atheroma progression. Previously, we demonstrated that thyronine analogs inhibit Cu2+-induced low density lipoprotein (LDL) oxidation. In the present study, we examined the effect of thyronine analogs on endothelial cell (EC)-induced LDL oxidation. LDL was incubated with or without EC in the presence or absence of various concentrations of thyronine, vitamin C, or probucol at 37 degrees in a humidified atmosphere (95% air, 5% CO2). Thyronine analogs, probucol, and vitamin C inhibited EC-induced LDL oxidation in a concentration-dependent manner. The concentration of each agent (mu M) producing 50% inhibition (IC50) of EC-induced LDL oxidation for thiobarbituric acid reactive substances (TEARS) and electrophoretic mobility, respectively, was as follows: 0.294 and 0.417 for levothyroxine (L-T-4); 0.200 and 0.299 for L-triiodothyronine (L-T-3); 0.125 and 0.264 for dextro-thyroxine (D-T-4); 0.203 and 0.304 for reversed triiodothyronine (rT(3)); 1.02 and 1.44 for probucol; and 13.6 and 14.9 for vitamin C. Thyroid binding globulin (TBG) inhibited EC-induced LDL oxidation; further, thyronines bound to TBG exhibited more antioxidant activity than unbound thyronines. Pretreatment of EC with any of the thyronines decreased the ability of EC to oxidize LDL. Also, our results showed that a synergistic interaction exists between vitamin C and T-4 in the inhibition of EC-induced LDL oxidation. The T-4 and TBG concentrations that inhibited LDL oxidation were in the physiological range. We conclude that T-4, like the pharmacological agent probucol, reduces oxidative modification of LDL and thus may act as a natural inhibitor of atherogenesis.