Oxidative stress increases the expression of the CD36 scavenger receptor and the cellular uptake of oxidized low-density lipoprotein in macrophages from atherosclerotic mice: protective role of antioxidants and of paraoxonase.
Little is known about the effects of oxidative stress on macrophage lipid peroxidation and on their atherogenic consequences. Therefore, we questioned the causal relationship between cellular lipid peroxides content and macrophage uptake of oxidized low-density lipoprotein (Ox-LDL). Lipid peroxide content in mouse peritoneal macrophages (MPMs) from E-deficient (E(0)) mice increased progressively by up to 4.6 fold during mice aging, and this was accompanied by an age-dependent increase in the cellular uptake of Ox-LDL (90%), and in the expression of the scavenger receptor CD36 mRNA (41%). Inhibition or stimulation of cellular oxidative stress by administration of dietary potent antioxidants (vitamin E or glabridin) or by inducing cellular glutathione depletion (by using buthionine sulfoximine), respectively, resulted in a significant increment or inhibition of macrophage uptake of Ox-LDL and in cellular CD36 mRNA expression, respectively. Intraperitoneal injection of human serum paraoxonase (PON1) into E(0) mice, resulted in a 40-65% decrement in the lipid peroxide content in MPM harvested from E(0) mice at 2-5 months of age, which subsequently resulted in a similar reduced uptake of Ox-LDL and expression of CD36 mRNA (by 30-40%). In conclusion, our results are the first to demonstrate that macrophage lipid peroxidation stimulates CD36 mRNA expression and enhances the cellular uptake of Ox-LDL.
Fuhrman
Bianca
B
The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences and Rambam Medical Center, Haifa 31096, Israel.
Volkova
Nina
N
Aviram
Michael
M
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001161:Arteriosclerosis / Q000378:metabolism / Q000517:prevention & control*; D043303:Aryldialkylphosphatase; D018955:CD36 Antigens / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004950:Esterases / Q000187:drug effects / Q000378:metabolism*; D007529:Isoflavones; D008077:Lipoproteins, LDL / Q000187:drug effects / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress; D010636:Phenols / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D012016:Reference Values; D012680:Sensitivity and Specificity; D014810:Vitamin E / Q000494:pharmacology*
D000975:Antioxidants; D018955:CD36 Antigens; D007529:Isoflavones; D008077:Lipoproteins, LDL; D010636:Phenols; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein; D014810:Vitamin E; D004950:Esterases; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; C107601:glabridin