Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro.
Oxidized LDL is implicated in atherosclerosis; however, the pathways that convert LDL into an atherogenic form in vivo are not established. Production of reactive nitrogen species may be one important pathway, since LDL recovered from human atherosclerotic aorta is enriched in nitrotyrosine. We now report that reactive nitrogen species generated by the MPO-H2O2-NO2- system of monocytes convert LDL into a form (NO2-LDL) that is avidly taken up and degraded by macrophages, leading to massive cholesterol deposition and foam cell formation, essential steps in lesion development. Incubation of LDL with isolated MPO, an H2O2-generating system, and nitrite (NO2-)-- a major end-product of NO metabolism--resulted in nitration of apolipoprotein B 100 tyrosyl residues and initiation of LDL lipid peroxidation. The time course of LDL protein nitration and lipid peroxidation paralleled the acquisition of high-affinity, concentration-dependent, and saturable binding of NO2-LDL to human monocyte-derived macrophages and mouse peritoneal macrophages. LDL modification and conversion into a high-uptake form occurred in the absence of free metal ions, required NO2-, occurred at physiological levels of Cl-, and was inhibited by heme poisons, catalase, and BHT. Macrophage binding of NO2-LDL was specific and mediated by neither the LDL receptor nor the scavenger receptor class A type I. Exposure of macrophages to NO2-LDL promoted cholesteryl ester synthesis, intracellular cholesterol and cholesteryl ester accumulation, and foam cell formation. Collectively, these results identify MPO-generated reactive nitrogen species as a physiologically plausible pathway for converting LDL into an atherogenic form.
Podrez
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EA
Department of Cell Biology, and Department of Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Schmitt
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D
Hoff
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HF
Hazen
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D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism*; D002788:Cholesterol Esters / Q000096:biosynthesis; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D015227:Lipid Peroxidation; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism*; D009585:Nitrogen Dioxide / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism*
D002788:Cholesterol Esters; D008077:Lipoproteins, LDL; D009573:Nitrites; D006861:Hydrogen Peroxide; D009195:Peroxidase; D009585:Nitrogen Dioxide