A role for endothelial cell lipoxygenase in the oxidative modification of low density lipoprotein.

Abstract

Oxidative modification of low density lipoprotein (LDL) has been implicated as a factor in the generation of macrophage-derived foam cells in vitro and in vivo. However, the exact mechanism of LDL oxidation has not been established. The present studies show that cellular lipoxygenase activity is involved in endothelial cell-induced oxidation of LDL. Inhibitors of lipoxygenase (but not inhibitors of cyclooxygenase) reduced LDL oxidation by as much as 70-85% under the conditions used. In contrast, the addition of pure (recombinant) superoxide dismutase inhibited by only =25% under the same conditions. Oxidation ofLDL by smooth muscle cells, on the other hand, was effectively inhibited by superoxide dismutase, as was Cu2+-catalyzed oxidation of LDL. When LDL was added to endothelial cell cultures within a dialysis bag, it did not undergo oxidative modification, suggesting that cell-LDL contact is necessary. We propose that an important element in cell-induced oxidation of LDL depends on (i) lipoxygenase oxidation of cellular lipids, followed by their exchange into LDL in the medium; (ii) direct lipoxygenasedependent oxidation of LDL lipids during LDL-cell contact; (iii) or both.

Mechanisms of H2O2-induced oxidative stress in endothelial cells

“…Lipoxygenase has been shown to produce O 2 ·-and is also associated with the arachidonic acid cascade (Parthasarathy et al 1989). It may play a role in the oxidation of LDL and formation of lipid free radicals, which are capable of scavenging NO (Parthasarathy et al 1989;Mertens et al 2001).…”

“…It may play a role in the oxidation of LDL and formation of lipid free radicals, which are capable of scavenging NO (Parthasarathy et al 1989;Mertens et al 2001). Lipoxygenase is also thought to contribute to angiotensin II activation of NADPH oxidase O 2 ·-formation during cardiovascular disease (Luchtefeld et al 2003).…”

Oxidative Modification of Low Density Lipoproteins by Human Polymorphonuclear Leukocytes

“…Stimulation of the cells with phorbol 12-myristate 13-acetate resulted in an increase both in Superoxide anion production and in low density lipoprotein oxidation. The present results show that the oxidative modification of low density lipoproteins by human polymorphonuclear leukocytes can be inhibited by Superoxide dismutase but not by the lipoxygenase inhibitor, (5,8,11,14)eicosatetraynoic acid. The low density lipoproteins oxidized by polymorphonuclear leukocytes were recognized by the scavenger receptor of macrophages (P 388 cell line).…”

“…In contrast, our results show that incubation of low density lipoproteins with human polymorphonuclear leukocytes leads to oxidatively modified low density lipoproteins which are recognized by the scavenger receptor of macrophages. Scavenger receptor-mediated uptake of modified low density lipoproteins must be considered more important for the development of artheroscler-otic plaques in vivo, since monocytes lose most of their low density lipoprotein receptor activity upon transformation to macrophages, which then express scavenger receptor activity (24 This mechanism of low density lipoprotein modification in polymorphonuclear leukocytes is in contrast to macrophages and endothelial cells where 15-lipoxygenase activity has been suggested to be responsible for the oxidative modification of low density lipoproteins (11,12).…”

“…It has been proposed cepted as one of the major risk factors contributing that the oxidative modification of low density lipoto the development of coronary heart disease. From proteins by cells can be mediated either by Superoxide epidemiological studies (1,2) and animal experiments anions (10), or by the action of the 15-lipoxygenase (3,4) it is clear that cholesterol is deposited in ath-^ enzyme (11,12). erosclerotic plaques and that this cholesterol is mainly T 1 t_^i u ι * t-i ι -.…”