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Oxidized Low Density Lipoproteins Alter Macrophage Lipid Uptake, Apoptosis, Viability and Nitric Oxide Synthesis¹

College of Physicians and Surgeons, Department of Medicine, Division of Cardiology, and Department of Pediatrics, Division of Gastroenterology, Columbia University, New York, NY 10032

Uptake of oxidized low density lipoproteins (LDL) by monocyte macrophages to form "foam" cells occurs during formation of atherosclerotic lesions. Inducible nitric oxide synthase (iNOS) has been identified in foam cells. To investigate interactions between oxidized LDL, monocyte macrophage viability and iNOS, studies were performed with J774.A1 macrophages. iNOS mRNA, protein and enzyme activity were induced in J774.A1 macrophages by IFN- and lipopolysaccharide (LPS). Neither iNOS induction nor inhibition of nitric oxide (NO) formation was associated with significant alterations in the binding, uptake or degradation of native or oxidized LDL. Nontoxic doses of native LDL or of oxidized LDL did not influence iNOS mRNA or protein in macrophages. However, oxidized LDL, but not native LDL or acetyl LDL, inhibited NO production by macrophages in a dose- and time-dependent fashion. Inhibition of iNOS was not correlated with cholesteryl ester formation but with the degree of LDL oxidation. Inhibition of iNOS did not require the scavenger receptor or directed endocytosis and exhibited noncompetitive kinetics. Inhibition of iNOS activity in J774.A1 macrophages was produced by lipid from oxidized LDL but not by lipid from native LDL and by PC vesicles containing LPC but not by PC vesicles alone. Inhibition of NO formation diminished apoptosis of the activated macrophages. The data suggest NO production by iNOS and inhibition of the enzyme by oxidized LDL lipid may influence cell viability, cell-cell interactions and vasomotor tone during atherogenesis.

KEY WORDS: • atherosclerosis • nitric oxide • macrophages • nitric oxide synthase • oxidized low density lipoproteins

¹ Presented as part of the symposium: "Formation, Metabolism and Physiologic Effects of Oxidatively Modified Low Density Lipoprotein" given at the Experimental Biology '95 meeting, Atlanta, GA, on April 12, 1995. This symposium was sponsored by the American Institute of Nutrition and was supported in part by Kraft General Foods, Inc. Guest editor for the symposium publication was Rachel Shireman, University of Florida, Gainesville, FL.

² To whom correspondence should be addressed: Columbia University, 630 West 168th Street, New York, NY 10032.