TOXICITY OF OXIDIZED LOW-DENSITY LIPOPROTEINS FOR VASCULAR SMOOTH-MUSCLE CELLS AND PARTIAL PROTECTION BY ANTIOXIDANTS

Oxidized low density lipoprotein (oxLDL) is known to be toxic to a var iety of cell types, but relatively little is known about the toxic eff ects of oxLDL on vascular smooth muscle cells (SMC). We found that LDL oxidized by incubation with 5 mu M cupric ions was toxic to cultured porcine SMC when administered al concentrations of 25 mu g protein/ml and higher. The toxicity was demonstrated whether cells were prolifera ting or not, and was more evident in the presence of 0.4% lipoprotein- deficient serum than in 10%. Because of recent evidence that 7-ketocho lesterol and 7-hydroxycholesterol are toxic species in copper-oxidized LDL, inhibition of 3-hydroxy-3-melhylglutaryl CoA (HMG-CoA) reductase was hypothesized as a mechanism of toxicity. However, mevalonic acid, the product of this enzyme, failed to protect against the toxicity of either oxLDL or the pure oxysterols. Alpha-tocopherol, alpha-tocopher ol acetate, probucol, butylated hydroxytoluene, and deferoxamine provi ded partial protection to SMC exposed to oxLDL. These results suggeste d a toxic role for newly initialed lipid peroxidation, either in cells or in media oxLDL. Cellular lipid peroxidation appeared more likely, since no further oxidation of media oxLDL was demonstrated in the pres ence or absence of antioxidants. Overall, the results suggest that tox icity of copper-oxidized LDL for SMC is multifactorial and differs fro m the previously described toxicity of iron-oxidized LDL for fibroblas ts.