Atorvastatin therapy in hypercholesterolemic patients suppresses cellular uptake of oxidized-LDL by differentiating monocytes.
Atherosclerosis is characterized by macrophage foam cells formation, which originate from differentiating blood monocytes that have taken up oxidized LDL (Ox-LDL) at enhanced rate. Statin therapy exhibit pleiotropic effects on many components of atherosclerosis. We have studied the effect of atorvastatin therapy in hypercholesterolemic patients, on the cellular uptake of Ox-LDL by their monocytes during differentiation into macrophages. Eleven hypercholesterolemic men were treated with 20 mg/day of atorvastatin for a period of 1 month. Peripheral blood monocytes harvested from control subjects and from patients before and after atorvastatin therapy were allowed to differentiate in culture for up to 9 days in the presence of 20% autologous serum. In control monocytes/macrophages the cellular uptake of Ox-LDL and the scavenger receptors CD36, SRA-I and SRA-II mRNA expression were upregulated during differentiation, and this upregulation was significantly enhanced in cells from hypercholesterolemic patients. Atorvastatin therapy suppressed the upregulation in Ox-LDL degradation and scavenger receptors expression in differentiating monocytes. These effects could be related at least in part to antioxidant characteristics of atorvastatin. Reduced susceptibility of plasma to free radical-induced lipid peroxidation (by 35%), increased plasma total antioxidant status (TAS; by 30%), and increased serum paraoxonase activity (by 53%), were noted following drug therapy. We conclude that atorvastatin therapy in hypercholesterolemic patients reduces the enhanced cellular uptake of Ox-LDL during ex-vivo differentiation of monocytes into macrophages, and decreases cellular scavenger receptors gene expression. These effects may account for the attenuation of atherogenesis in hypercholesterolemic patients following atorvastatin treatment.
Fuhrman
Bianca
B
The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences and Rambam Medical Center, 31096, Haifa, Israel. fuhrman@tx.technion.ac.il
Koren
Lena
L
Volkova
Nina
N
Keidar
Shlomo
S
Hayek
Tony
T
Aviram
Michael
M
D000328:Adult; D000069059:Atorvastatin; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006937:Hypercholesterolemia / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D011758:Pyrroles / Q000494:pharmacology*; D012313:RNA / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D051116:Receptors, Scavenger
D018955:CD36 Antigens; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; D011758:Pyrroles; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; C099252:oxidized low density lipoprotein; D012313:RNA; D000069059:Atorvastatin