LOVASTATIN INHIBITS LOW-DENSITY-LIPOPROTEIN OXIDATION AND ALTERS ITS FLUIDITY AND UPTAKE BY MACROPHAGES - INVITRO AND INVIVO STUDIES

Under experimental conditions, oxidized low-density lipoprotein (Ox-LDL) may possess atherogenic properties, as is evidenced by its contribution to cholesterol accumulation in macrophages. LDL was oxidized in a cell-free system by predialysis of the lipoprotein against EDTA-free buffer and the addition of copper ions. Oxidation of LDL in the presence of lovastatin (10 to 1,000 μmol/L) resulted in a time- and dose-dependent reduction in thiobarbituric-acid-reactive substances (TBARS) concentration that was accompanied by increased LDL lysine-amino-group reactivity, in comparison with Ox-LDL produced in the absence of lovastatin. At 100 μmol/L, the drug reduced malondialdehyde concentration and increased amino-group reactivity by 24% and 42%, respectively. However, lovastatin's antioxidant effect was limited relative to other antioxidants, such as probucol and vitamin E. The fluidity of Ox-LDL was substantially reduced in comparison with native LDL. However, lovastatin inhibited this reduction in fluidity by 20%. Upon incubation of J-774 macrophage-like cell line with Ox-LDL, the lovastatin-treated Ox-LDL induced a reduction in the cellular cholesterol esterification rate in comparison with the effect of Ox-LDL that was produced in the absence of the drug. In four patients with hypercholesterolemia, the effect of lovastatin therapy (20 mg/d) on the sensitivity of their LDL to in vitro oxidation was studied. In all patients, Ox-LDL prepared from LDL obtained during lovastatin treatment demonstrated a reduced TBARS content, an increased trinitrobenzenesulfonic acid (TNBS) reactivity, an increased fluidity, and an impaired uptake by macrophages. These results were similar to those obtained by adding lovastatin in vitro. Thus lovastatin, in addition to its cholesterol-lowering effect, has antioxidant properties that may inhibit production of atherogenic Ox-LDL. © 1992.