Prevention by alpha-tocopherol and rutin of glutathione and ATP depletion induced by oxidized LDL in cultured endothelial cells.
1. Oxidized low density lipoproteins (LDL) are thought to play an important role in atherogenesis. Mildly oxidized LDL are cytotoxic to cultured endothelial cells. Toxic doses of oxidized LDL promote the peroxidation of cellular lipids (beginning at 6 h and being maximal after 12 h of pulse with oxidized LDL) and glutathione and ATP depletion (beginning after 15 h of pulse and evolving concurrently with the cytotoxicity). 2. Antioxidants from 3 different classes (rutin, ascorbic acid and alpha-tocopherol) were compared as to their ability to inhibit the cytotoxic effect of oxidized LDL to endothelial cells. 3. Effective concentrations of alpha-tocopherol inhibited cellular lipid peroxidation, glutathione and ATP depletion and the cytotoxic effect. 4. Ascorbic acid was less effective than alpha-tocopherol and rutin, and exhibited a dose-dependent biphasic effect in the presence of oxidized LDL. 5. Effective concentrations of rutin inhibited glutathione and ATP depletion as well as cytotoxicity, but did not block cellular lipid peroxidation. This suggests that the glutathione and ATP depletion is directly correlated to the cytotoxicity of oxidized LDL, whereas cellular lipid peroxidation is probably not directly the cause of cellular damage leading to cell death. 6. The association of antioxidants of 3 different classes allowed the suppression of the biphasic effect of ascorbic acid and increased the efficacy of the protective effect. The potential consequences for prevention of the pathogenic role of oxidized LDL in endothelial injury are discussed.
Schmitt
A
A
Department of Biochemistry-Metabolic Disease Laboratory, University Paul Sabatier, Toulouse, France.
Salvayre
R
R
Delchambre
J
J
Nègre-Salvayre
A
A
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology; D002417:Cattle; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004727:Endothelium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D012431:Rutin / Q000494:pharmacology*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology*
D000975:Antioxidants; D008077:Lipoproteins, LDL; D017392:Thiobarbituric Acid Reactive Substances; D014810:Vitamin E; D012431:Rutin; D000255:Adenosine Triphosphate; D005978:Glutathione; D001205:Ascorbic Acid