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Superoxide Initiates Oxidation of Low Density Lipoprotein by Human Monocytes

Superoxide Initiates Oxidation of Low Density Lipoprotein by Human Monocytes Human mononuclear cells were used to evaluate the role of superoxide in the oxidation of low density lipoprotein (LDL). Unstimulated cells produced little superoxide or LDL oxidation as assayed by lipid peroxide content. Stimulation of the cells with phorbol myristate acetate (PMA) resulted in an increase both in superoxide production and in LDL oxidation. Mononuclear cell‐mediated LDL oxidation was time‐ and cell number‐dependent and was markedly enhanced by the presence of Fe (10 &mgr;M). Superoxide was required for theinitiationof LDL oxidation as indicated by inhibition of the reaction by early addition of superoxide dismutase (SOD).Propagationof LDL oxidation was superoxide‐independent, since the later addition of SOD resulted in progressively less inhibition of LDL oxidation. Propagation of LDL oxidation also was, in part, cell‐independent as indicated by continued oxidation of LDL when mononuclear cells were removed following a 1 to 8 hour period with cells. Optimal LDL oxidation required the presence of mononuclear cells throughout the incubation period, suggesting that cellular factors in addition to superoxide play a role in LDL oxidation. Further evidence for the role of superoxide in the oxidation of LDL by mononuclear cells was obtained with cells from patients with genetic deficiencies of either superoxide generation (chronic granulomatous disease) or myeloperoxidase. PMA‐stimulated cells from a patient with chronic granulomatous disease neither generated superoxide nor modified LDL. Incubation of LDL with cells from a patient with myeloperoxidase deficiency (in which superoxide production is normal or increased) resulted in oxidation of the lipoprotein equivalent to that observed with normal cells. Other inhibitors of oxidation reactions also were tested. Catalase, desferrioxamine, and EDTA partially inhibited LDL oxidation by mononuclear cells, while the hydroxyl radical scavenger, mannitol, was without effect. The general free radical scavenger, butylated hydroxytoluene, completely inhibited LDL oxidation. These findings suggest that LDL oxidation by human mononuclear cells is mediated by superoxide. Although superoxide is necessary for the initiation of LDL oxidation, progression of lipid peroxidation appears to be independent of superoxide. Oxidation of LDL by mononuclear cells is transition metal‐dependent and occurs by a free radical process similar to that observed with arterial smooth muscle cells. However, in contrast to smooth muscle cell‐modified LDL, mononuclear cell‐modified LDL or acetylated LDL resulted in less stimulation of cholesteryl ester synthesis by macrophages than did control lipoproteins. (Arteriosclerosis 7:55‐60, January/February 1987) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Arteriosclerosis Wolters Kluwer Health

Superoxide Initiates Oxidation of Low Density Lipoprotein by Human Monocytes

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ISSN
0276-5047

Abstract

Human mononuclear cells were used to evaluate the role of superoxide in the oxidation of low density lipoprotein (LDL). Unstimulated cells produced little superoxide or LDL oxidation as assayed by lipid peroxide content. Stimulation of the cells with phorbol myristate acetate (PMA) resulted in an increase both in superoxide production and in LDL oxidation. Mononuclear cell‐mediated LDL oxidation was time‐ and cell number‐dependent and was markedly enhanced by the presence of Fe (10 &mgr;M). Superoxide was required for theinitiationof LDL oxidation as indicated by inhibition of the reaction by early addition of superoxide dismutase (SOD).Propagationof LDL oxidation was superoxide‐independent, since the later addition of SOD resulted in progressively less inhibition of LDL oxidation. Propagation of LDL oxidation also was, in part, cell‐independent as indicated by continued oxidation of LDL when mononuclear cells were removed following a 1 to 8 hour period with cells. Optimal LDL oxidation required the presence of mononuclear cells throughout the incubation period, suggesting that cellular factors in addition to superoxide play a role in LDL oxidation. Further evidence for the role of superoxide in the oxidation of LDL by mononuclear cells was obtained with cells from patients with genetic deficiencies of either superoxide generation (chronic granulomatous disease) or myeloperoxidase. PMA‐stimulated cells from a patient with chronic granulomatous disease neither generated superoxide nor modified LDL. Incubation of LDL with cells from a patient with myeloperoxidase deficiency (in which superoxide production is normal or increased) resulted in oxidation of the lipoprotein equivalent to that observed with normal cells. Other inhibitors of oxidation reactions also were tested. Catalase, desferrioxamine, and EDTA partially inhibited LDL oxidation by mononuclear cells, while the hydroxyl radical scavenger, mannitol, was without effect. The general free radical scavenger, butylated hydroxytoluene, completely inhibited LDL oxidation. These findings suggest that LDL oxidation by human mononuclear cells is mediated by superoxide. Although superoxide is necessary for the initiation of LDL oxidation, progression of lipid peroxidation appears to be independent of superoxide. Oxidation of LDL by mononuclear cells is transition metal‐dependent and occurs by a free radical process similar to that observed with arterial smooth muscle cells. However, in contrast to smooth muscle cell‐modified LDL, mononuclear cell‐modified LDL or acetylated LDL resulted in less stimulation of cholesteryl ester synthesis by macrophages than did control lipoproteins. (Arteriosclerosis 7:55‐60, January/February 1987)

Journal

Arteriosclerosis – Wolters Kluwer Health

Published: Jan 1, 1987

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