9433906

pubmed:Citation

2

Macrophage-mediated oxidation of low-density lipoprotein (LDL) is thought to play a key role during early atherogenesis, and cellular oxygenases were shown to mediate this process. As macrophage antioxidants may also contribute to the extent of cell-mediated oxidation of LDL, we analyzed the role of cellular reduced glutathione (GSH) and glutathione peroxidase (GPx) in LDL oxidation. The present study examined the effect of the macrophage GSH-GPx status on the ability of the cells to oxidize LDL. Upon incubation of J-774 A.1 macrophages for 20 h at 37 degrees C with 50 microM of buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, cellular GSH content and GPx activity were reduced by 89 and 50%, respectively, and this effect was associated with a twofold elevation in macrophage-mediated oxidation of LDL. The BSO-treated cells contained high levels of peroxides, and released 32% more superoxide anions than nontreated cells in response to their stimulation with LDL in the presence of copper ions. To increase macrophage GSH content and GPx activity we have used L-2-oxothiazolidine-4-carboxylic acid (OTC), which delivers cysteine residues to the cells for GSH synthesis, and also selenium, which activates GPx and increases cellular glutathione synthesis. GSH content and GPx activity in J-774 A.1 macrophages were increased by 80 and 50%, respectively, following cells incubation with 2 mM OTC for 20 h at 37 degrees C, and this was paralleled by a 47% inhibition in LDL oxidation by these cells. An inverse correlation was found between the extent of macrophage-mediated oxidation of LDL and cellular GSH content (r = .97), or GPx activity (r = .95). Upon incubation of J-774 A.1 macrophages with selenomethionine (10 ng/ml) for 1 week, cellular GSH content and GPx activity were increased by about twofold compared to control cells, and this effect was associated with a 30% reduction in cell-mediated oxidation of LDL. Dietary selenium supplementation (1 microg/d/mouse) to the atherosclerotic apolipoprotein E-deficient mice for a 6-month period, increased GSH content and GPx activity in the mice peritoneal macrophages by 36 and 30%, respectively, and this effect was associated with a 46% reduction in cell-mediated oxidation of LDL. Finally, the atherosclerotic lesion area in the aortas derived from these mice after selenium supplementation was found to be reduced by 30% compared to the lesion area found in nontreated mice. Our results demonstrate an inverse relationship between macrophage GSH content/GPx activity and cell-mediated oxidation of LDL. Intervention means to enhance the macrophage GSH-GPx status may thus contribute to attenuation of the atherosclerotic process.

http://linkedlifedata.com/resource/pubmed/journal/8709159

http://linkedlifedata.com/resource/pubmed/chemical/2-oxothiazolidine-4-carboxylic acid, http://linkedlifedata.com/resource/pubmed/chemical/Apolipoproteins E, http://linkedlifedata.com/resource/pubmed/chemical/Buthionine Sulfoximine, http://linkedlifedata.com/resource/pubmed/chemical/Glutathione, http://linkedlifedata.com/resource/pubmed/chemical/Glutathione Peroxidase, http://linkedlifedata.com/resource/pubmed/chemical/Lipoproteins, LDL, http://linkedlifedata.com/resource/pubmed/chemical/Peroxides, http://linkedlifedata.com/resource/pubmed/chemical/Pyrrolidonecarboxylic Acid, http://linkedlifedata.com/resource/pubmed/chemical/Selenium, http://linkedlifedata.com/resource/pubmed/chemical/Superoxides, http://linkedlifedata.com/resource/pubmed/chemical/Thiazoles, http://linkedlifedata.com/resource/pubmed/chemical/Thiazolidines, http://linkedlifedata.com/resource/pubmed/chemical/oxidized low density lipoprotein

Jan

pubmed-author:AviramMM, pubmed-author:RosenblatMM

15

NLM

305-17

pubmed-meshheading:9433906-Animals, pubmed-meshheading:9433906-Apolipoproteins E, pubmed-meshheading:9433906-Arteriosclerosis, pubmed-meshheading:9433906-Buthionine Sulfoximine, pubmed-meshheading:9433906-Cell Line, pubmed-meshheading:9433906-Glutathione, pubmed-meshheading:9433906-Glutathione Peroxidase, pubmed-meshheading:9433906-Lipoproteins, LDL, pubmed-meshheading:9433906-Macrophages, pubmed-meshheading:9433906-Macrophages, Peritoneal, pubmed-meshheading:9433906-Mice, pubmed-meshheading:9433906-Mice, Transgenic, pubmed-meshheading:9433906-Oxidation-Reduction, pubmed-meshheading:9433906-Peroxides, pubmed-meshheading:9433906-Pyrrolidonecarboxylic Acid, pubmed-meshheading:9433906-Selenium, pubmed-meshheading:9433906-Superoxides, pubmed-meshheading:9433906-Thiazoles, pubmed-meshheading:9433906-Thiazolidines

Macrophage glutathione content and glutathione peroxidase activity are inversely related to cell-mediated oxidation of LDL: in vitro and in vivo studies.

Journal Article