A 21-aminosteroid inhibits oxidation of human low density lipoprotein by human monocytes and copper

Abstract

Oxidation of low density lipoprotein (LDL) leads to more rapid uptake by arterial wall macrophages and foam cell formation. Inhibiting LDL oxidation may impede these processes and offers a new mechanism to retard atherogenesis. The 21-aminosteroids, derived from methylprednisolone, are potent inhibitors of free radical production by stimulated monocytes and also are scavengers of lipid peroxyl radicals. The 21-aminosteroid, U74500A, was added to a mixture of low density lipoprotein cholesterol and human monocytes to which lipopolysaccharide was add to stimulate the monocytes. At a final concentration of 10 μM, U74500A reduced the production of lipid peroxidation from 6.10 ± 1.11 to 0.84 ± 0.16 nmol (mean ± SEM) MDA equivalent/1 × 10 6 monocytes, as measured by a thiobarbituric acid reacting substance (TBARS) assay. Similarly 10 μm U74500A reduced Cu 2+ induced LDL oxidation from 12.28 ± 0.10 (in vehicle) to 0.49 ± 0.12. These observations suggest that the 21-aminosteroids should be evaluated in animal models as a potential therapy to retard atherogenesis, especially considering their apparent lack of mineralocorticoid and glucocorticoid side-effects.