Effects of prostaglandins and nitric oxide on rat macrophage lipid metabolism in culture: Implications for arterial wall leukocyte interplay in atherosclerosis

Macrophages/foam cells have a pivotal role in atherogenesis although little is known about the way lipid imbalance, a hallmark of atherosclerosis, lea ds to lipid accumulation in these cells. Modified low-density lipoproteins are associated with macrophage lipid dysfunction in atherosclerosis, but a possible role for altered lipogenesis leading to lipid accumulation remains to be elucidated. Since endothelium-derived nitric oxide (NO) and prostagl andins (PGs) are physiological autacoids whose production may be impaired i n atherosclerosis, the effects of these mediators on de novo lipid synthesi s in 24-h cultured rat peritoneal macrophages is investigated. In resident (unstimulated) cells, 1 mu M PGE(2) and the stable analog of PGI(2) carbapr ostacyclin (cPGI(2), 1 mu M) deviated the overall [1-C-14]acetate from inco rporation into cholesterol, free fatty acids and triacylglycerols favoring the formation of phospholipids. In inflammatory (thioglycollate-elicited) m acrophages, these eicosanoids likewise reduced C-14-incorporations into all the lipid fractions tested. Also, cPGI(2) and PGE(2) reduced [4-C-14]chole sterol uptake from inflammatory cells but did not interfere in C-14-cholest erol export. The PGE(2)-derivative PGA(2) (10-20 mu M) reduced C-14- incorp orations into all the lipids in resident cells while it enhanced phospholip id synthesis by up to 129% at the expense of reduced incorporations into th e other test lipids. The NO donor S-nitroso-N-acetylpenicillamine (SNAP, 1- 10 mu M), when added to macrophages in the presence of superoxide dismutase (SOD, to avoid the reaction of superoxide with NO), significantly reduced lipogenesis especially in inflammatory cells. These findings suggest that e ndothelium-derived NO and PGs may be associated with macrophage lipid accum ulation by modulating lipogenesis and cholesterol uptake within these cells .