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 significa nt role in inhibiting a critical step in atheroma progression. Previou sly, we demonstrated that thyronine analogs inhibit Cu2+-induced low d ensity lipoprotein (LDL) oxidation. In the present study, we examined the effect of thyronine analogs on endothelial cell (EC)-induced LDL o xidation. LDL was incubated with or without EC in the presence or abse nce of various concentrations of thyronine, vitamin C, or probucol at 37 degrees in a humidified atmosphere (95% air, 5% CO2). Thyronine ana logs, 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 thiob arbituric acid reactive substances (TEARS) and electrophoretic mobilit y, 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 triiodothyr onine (rT(3)); 1.02 and 1.44 for probucol; and 13.6 and 14.9 for vitam in C. Thyroid binding globulin (TBG) inhibited EC-induced LDL oxidatio n; further, thyronines bound to TBG exhibited more antioxidant activit y than unbound thyronines. Pretreatment of EC with any of the thyronin es decreased the ability of EC to oxidize LDL. Also, our results showe d that a synergistic interaction exists between vitamin C and T-4 in t he inhibition of EC-induced LDL oxidation. The T-4 and TBG concentrati ons that inhibited LDL oxidation were in the physiological range. We c onclude that T-4, like the pharmacological agent probucol, reduces oxi dative modification of LDL and thus may act as a natural inhibitor of atherogenesis.