Lovastatin Decreases the Receptor-Mediated Degradation of Acetylated and Oxidized LDLs in Human Blood Monocytes During the Early Stage of Differentiation Into Macrophages

Abstract

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-...

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HMG-CoA Reductase Inhibitors Inhibit Inducible Nitric Oxide Synthase Gene Expression in Macrophages

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