title: Toxicity of oxidized low density lipoproteins for vascular smooth muscle cells and partial protection by antioxidants.
abstract: Oxidized low density lipoprotein (oxLDL) is known to be toxic to a variety of cell types, but relatively little is known about the toxic effects of oxLDL on vascular smooth muscle cells (SMC). We found that LDL oxidized by incubation with 5 microM cupric ions was toxic to cultured porcine SMC when administered at concentrations of 25 micrograms protein/ml and higher. The toxicity was demonstrated whether cells were proliferating or not, and was more evident in the presence of 0.4% lipoprotein-deficient serum than in 10%. Because of recent evidence that 7-ketocholesterol and 7-hydroxycholesterol are toxic species in copper-oxidized LDL, inhibition of 3-hydroxy-3-methylglutaryl 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-tocopherol acetate, probucol, butylated hydroxytoluene, and deferoxamine provided partial protection to SMC exposed to oxLDL. These results suggested a toxic role for newly initiated 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 presence or absence of antioxidants. Overall, the results suggest that toxicity of copper-oxidized LDL for SMC is multifactorial and differs from the previously described toxicity of iron-oxidized LDL for fibroblasts.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Guyton
authors.forename: M L
authors.initials: ML
authors.lastname: Lenz
authors.forename: B
authors.initials: B
authors.lastname: Mathews
authors.forename: H
authors.initials: H
authors.lastname: Hughes
authors.forename: D
authors.initials: D
authors.lastname: Karsan
authors.forename: E
authors.initials: E
authors.lastname: Selinger
authors.forename: C V
authors.initials: CV
authors.lastname: Smith
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001011:Aorta; D002084:Butylated Hydroxytoluene / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D003300:Copper / Q000494:pharmacology; D003470:Culture Media / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006888:Hydroxycholesterols / Q000633:toxicity; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007653:Ketocholesterols / Q000633:toxicity; D015227:Lipid Peroxidation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000187:drug effects / Q000633:toxicity*; D008148:Lovastatin / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010084:Oxidation-Reduction; D011341:Probucol / Q000494:pharmacology; D013552:Swine; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D014810:Vitamin E / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D003470:Culture Media; D004791:Enzyme Inhibitors; D006888:Hydroxycholesterols; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007653:Ketocholesterols; D008077:Lipoproteins, LDL; D017392:Thiobarbituric Acid Reactive Substances; D014810:Vitamin E; D002084:Butylated Hydroxytoluene; C011724:cholest-5-en-3 beta,7 alpha-diol; D003300:Copper; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D003676:Deferoxamine; C003001:7-ketocholesterol; D011341:Probucol; D008798:Mevalonic Acid