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

Abstract

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 μM PGE2 and the stable analog of PGI2 carbaprostacyclin (cPGI2, 1 μM) deviated the overall [1‐14C]acetate from incorporation into cholesterol, free fatty acids and triacylglycerols favoring the formation of phospholipids. In inflammatory (thioglycollate‐elicited) macrophages, these eicosanoids likewise reduced tac‐incorporations into all the lipid fractions tested. Also, cPGI2 and PGE2 reduced [4‐14C]cholesterol uptake from inflammatory cells but did not interfere in 14C‐cholesterol export. The PGE2‐derivative PGA2 (10‐20 μM) reduced 14C‐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 μM), 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 ceils.

Effect of Veratric Acid on the Cardiovascular Risk of L-NAME–induced Hypertensive Rats

“…The apparently close relationship between nitric oxide (data not shown) and cholesterol values found in this study is in line with previous observations that reduced nitric oxide availability increases the incorporation of labeled precursors in cholesterol molecules. 40 Increased LDL-C concentration in plasma may be due to the defect in LDL-C receptor either through failure in its production or function. HDL-C may be protective by reversing cholesterol transport, inhibiting the oxidation of LDL-C, and by neutralizing the atherogeneic effects of oxidized LDL-C. HDL-C helps to scavenge cholesterol from extrahepatic tissues in the presence of LCAT and brings it to the liver.…”

“…Different doses of VA (20,40, and 80 mg/kg of body weight) were assessed to find out the antihypertensive/ antioxidant effect of VA in L-NAME-induced hypertension. VA at a dose of 40 mg/kg of body weight has shown potent antihypertensive/antioxidant in L-NAME-treated rats as compared with rest of the doses.…”

Cyclooxygenase-1 Deficiency in Bone Marrow Cells Increases Early Atherosclerosis in Apolipoprotein E– and Low-Density Lipoprotein Receptor–Null Mice

“…13 Macrophage PGI 2 reduces cholesterol uptake and foam cell formation but does not interfere with cholesterol export. 33 In addition, PGI 2 analogues dose-dependently inhibited production of inflammatory cytokines (tumor necrosis factor-␣, interleukin-1␤, and granulocyte-macrophage colony-stimulating factor) by human alveolar macrophages. 34,35 Thus, the suppression of PGI 2 production in COX-1 Ϫ/Ϫ macrophages in the present studies may accelerate the development of atherosclerosis by promoting foam cell formation and the production of inflammatory cytokines.…”

Oxidant stress in the vasculature

“…Superoxide and peroxynitrite act in concert to ox-LDL production and induce endoth e l i a l d ys f u n c t i o n . M a c r o p h a g e s s t i m u l a t e d by thioglycollate in the presence of superoxide dismutase exhibited a significant reduction in lipogenesis [63]. ox-LDL additionally stimulates the synthesis of lactosylceramide, a glycosphingolipid found at high concentration in fatty streaks and intimal plaque.…”