Native LDL and LDL oxidized under various conditions were compared in terms of their ability to activate platelets. Native LDL did not induce platelet shape change or aggregation, even at high concentrations (2 mg protein/mL). LDL was mildly oxidized with either CuSO4 (mox-LDL) or 3-(N-morpholino)sydnonimine (SIN-1-LDL). Analysis of mox-LDL and SIN-1-LDL showed a small increase of dienes (E234nm from 0.28 +/- 0.04 to 0.55 +/- 0.09, mean +/- SD) and thiobarbituric acid-reactive substance (from 0 to 10.6 +/- 1.5 nmol/mg, mean +/- SEM), no change in apo B electrophoretic mobility, and a minor (12% to 30%) decrease in polyunsaturated fatty acid content. Interestingly, this small oxidative modification of LDL dramatically changed its effect on platelets. Irreversible aggregation and secretion were induced by a threshold concentration of 0.4 mg protein/mL. In contrast, LDL thoroughly oxidized with CuSO4 (ox-LDL) did not aggregate platelets. Although mox-LDL was depleted in antioxidants (alpha- and gamma-tocopherol, alpha- and beta-carotene, and other carotenoids), incubation of mox-LDL with exogenous alpha-tocopherol did not reverse its ability to induce platelet aggregation and secretion. Preincubation of platelets with the cyclooxygenase inhibitor aspirin or the phospholipase A2 inhibitors trifluoperazine, quinacrine, 4-bromophenacyl bromide, and propranolol completely prevented platelet aggregation and secretion caused by mox-LDL or SIN-1-LDL. These results indicate that mildly oxidized LDL activates platelets through a phospholipase A2/cyclooxygenase-dependent pathway. The complete inhibition of mox-LDL-induced platelet aggregation by aspirin could contribute to its beneficial effect in cardiovascular disease.

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Addition of fish oils to infant formula provides (n-3) long-chain polyenoic fatty acids (LCP), specifically 22:6(n-3), to infants fed formula rather than human milk. Most fish oils, however, contain high levels of 20:5(n-3) and low (n-6) LCP. These studies determined the brain total, synaptic plasma membrane phosphatidylethanolamine and phosphatidylcholine, and plasma and liver phospholipid fatty acids of piglets fed from birth to 15 d with formula containing (percent fatty acids) 34% 18:2(n-6), 0.8% 18:3(n-3) and 0, 2 or 6 g/L menhaden oil, or sow milk. The brain 22:6(n-3) was higher and 22:4(n-6) lower in piglets fed 6 g/L menhaden oil compared with sow milk. Brain levels of 20:5(n-3) did not increase, or levels of 20:4(n-6) decrease, with increasing dietary (n-3) LCP. A diet concentration-dependent increase in 20:5(n-3) and decrease in 20:4(n-6) (P less than 0.0001) in liver phospholipid showed no evidence of maximum saturation or depletion, respectively, over the range of (n-3) LCP intake studied. The fish oil supplementation was effective in supplying 22:6(n-3) to the developing brain. The accompanying increase in 20:5(n-3) and decrease in 20:4(n-6), important eicosanoid precursors, in plasma and liver phospholipid show the need for caution in the use of fish oils low in (n-6) LCP as a source of (n-3) LCP for infant formula.

Abstract-3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors are used therapeutically to upregulate the LDL receptor-mediated removal of plasma cholesterol by the liver. Several lines of evidence indicate that these drugs also exert direct effects on the metabolism of native and modified LDL in extrahepatic cells. We studied the effects of lovastatin (LOV) on the degradation of native, acetylated, and oxidized LDL, and on levels of mRNA encoding for the LDL, types I and II class A macrophage scavenger, and CD36 receptors in human blood monocytes at different stages of their maturation into adherent macrophages. LOV (10 mol/L) reduced the degradation of acetylated LDL when added to freshly isolated cells cultured for 2 (81Ϯ4% of control, PϽ0.05) and 5 (76Ϯ6%, of control, PϽ0.05) days. The degradation of oxidized LDL was also reduced in cells treated with LOV for 2 days after seeding (51Ϯ3% of control, PϽ0.001) but not in 5-day-old cells. LOV had no significant effect on the degradation of either acetylated or oxidized LDL when added to fully matured macrophages allowed to differentiate under control conditions for 7 days before incubations with 10 mol/L LOV for an additional 2 days. In contrast, LOV increased the degradation of native LDL in these cells at all 3 stages of cell differentiation. LOV also reduced class A types I and II macrophage scavenger receptor and CD36 mRNA levels in 2-and 5-day-old cells but not in the more mature macrophages. These data suggest that 3-hydroxy-3-methylglutaryl-coenzyme A inhibitors may reduce the expression and function of the class A types I and II macrophage scavenger receptor and CD36 in monocytes, during the early stages of their differentiation into adherent macrophages. These effects, if operative in vivo, may slow down the development of the atherosclerotic plaque and thus contribute to the beneficial effects of these drugs. Key Words: scavenger receptor Ⅲ LDL receptor Ⅲ acetylated LDL Ⅲ oxidized LDL Ⅲ CD36 Ⅲ 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor Ⅲ monocyte A key process in the pathogenesis of atherosclerosis is the adhesion and migration of blood monocytes into the vessel wall, 1 followed by their conversion into adherent macrophages and foam cells by the unregulated uptake of modified lipoproteins, through the so-called scavenger receptors. 2,3 Of the many cell surface proteins discussed as scavenger receptors, the class A types I and II macrophage scavenger receptor (SR-A) and CD36 have been shown to be responsible for the uptake of modified lipoproteins by human blood monocyte-derived macrophages (HMDMs). 4 -6 SR-A exhibits high affinity for both the chemically modified acetylated (acetyl) LDL and oxidized (ox) LDL, the latter of which is formed in vivo and is involved in atherogenesis. 7 Studies in SR-A-negative mice have recently confirmed the involvement of this receptor in the development of the atherosclerotic plaque 8 and elevated SR-A mRNA have been observed in freshly isolated mononuclear cells of hyperlipidemic patients. 9 The 88-...

The effect of feeding sow-milk formula (SMF) or a vegetable-oil infant formula (FF) with minimal n-6 and n-3 long-chain polyenoic fatty acids (LCPs) but high linoleic acid (18:2n-6) and a high ratio of 18:2n-6 to linolenic acid (18:3n-3) on the fatty acids of brain lipid and liver, plasma, and red cell phospholipids was studied in piglets fed from birth for 5, 10, 15, or 25 d. Compared with SMF, FF reduced the concentrations of 18:1 and n-3 LCPs, especially 22:6n-3, in all tissues and increased 22:4n-6 in brain, liver, plasma, and red cell phosphatidylethanolamine. FF also increased 22:5n-6 in brain lipid, liver, and plasma but not in red cell phospholipids. Thus, changes in tissues capable of in situ desaturation were not completely reflected in the red cell phospholipids. The increased liver and brain n-6 LCP accretion in the FF piglets may suggest competent desaturation and possible inhibition of n-3 desaturation and/or acylation by dietary n-6 fatty acids.