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, leads 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 prostaglandins (PGs) are physiological autacoids whose production may be impaired in atherosclerosis, the effects of these mediators on de novo lipid synthesis 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) carbaprostacyclin (cPGI(2), 1 mu M) deviated the overall [1-C-14]acetate from incorporation into cholesterol, free fatty acids and triacylglycerols favoring the formation of phospholipids. In inflammatory (thioglycollate-elicited) macrophages, these eicosanoids likewise reduced C-14-incorporations into all the lipid fractions tested. Also, cPGI(2) and PGE(2) reduced [4-C-14]cholesterol uptake from inflammatory cells but did not interfere in C-14-cholesterol export. The PGE(2)-derivative PGA(2) (10-20 mu M) reduced C-14- incorporations into all the lipids in resident cells while it enhanced phospholipid synthesis by up to 129% at the expense of reduced incorporations into the 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 endothelium-derived NO and PGs may be associated with macrophage lipid accumulation by modulating lipogenesis and cholesterol uptake within these cells.