The participation of nitric oxide in cell free- and its restriction of macrophage-mediated oxidation of low-density lipoprotein.
The potential role of nitric oxide radical (NO .) in macrophage-mediated oxidation and conversion of human low density lipoprotein (LDL) to a high-uptake form was examined by exposing LDL to aerobic solutions of either NO . or 3-morpholino-sydnonimine-hydrochloride (SIN-1, a compound that spontaneously forms NO . and superoxide anion radical) or to mouse peritoneal macrophages in the presence and absence of modulators of cellular NO . synthesis. Incubation with NO . alone caused oxidation of LDL's ubiquinol-10 and accumulation of small amounts of lipid hydroperoxides, but failed to form any high-uptake ligand for endocytosis by macrophages and did not alter the LDL particle charge or the integrity of apoB. Exposure of LDL to SIN-1 resulted in complete consumption of all antioxidants and substantial formation of lipid hydroperoxides, but again had little effect on the lipoprotein particle charge or generation of high-uptake form. Preincubation of macrophages with interferon-gamma increased the cells ability to generate reactive nitrogen metabolites. The extent of cell-mediated oxidation of LDL and the generation of high-uptake LDL was substantial in resident cells in which NO . synthesis was barely detectable, depressed in cells active in NO . synthesis and restored when NO . synthesis was suppressed by the arginine analogue, NMMA. These results suggest that, while together with superoxide anion radical, NO . can oxidize LDL, its synthesis is not required for macrophage-mediated oxidation of LDL in vitro; rather it exerts a protective role in preventing oxidative LDL modification by macrophages.
Jessup
W
W
Cell Biology Group, Heart Research Institute, Sydney, Australia.
Mohr
D
D
Gieseg
S P
SP
Dean
R T
RT
Stocker
R
R
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002474:Cell-Free System; D002478:Cells, Cultured; D004705:Endocytosis; D005609:Free Radicals; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D010084:Oxidation-Reduction; D010529:Peritoneal Cavity / Q000166:cytology; D013481:Superoxides / Q000378:metabolism
D000975:Antioxidants; D005609:Free Radicals; D008077:Lipoproteins, LDL; D009573:Nitrites; D013481:Superoxides; D009569:Nitric Oxide; C002385:linsidomine; D008981:Molsidomine