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Decreased Macrophage Paraoxonase 2 Expression in Patients With Hypercholesterolemia Is the Result of Their Increased Cellular Cholesterol Content: Effect of Atorvastatin Therapy

Objective—To analyze paraoxonase2 (PON2) expression in human monocyte-derived macrophages (HMDM) from patients with hypercholesterolemia in relation to cellular cholesterol and oxidative stress. Methods and Results—Ten healthy subjects (controls) and 10 patients with hypercholesterolema who received 20-mg/d atorvastatin participated in the study. The patients’ versus controls’ HMDM demonstrated increased cholesterol content (270%) and oxidative stress (30% to 45%). Atorvastatin therapy reduced these parameters (59% and 25%, respectively). The patients’ versus controls’ macrophage-PON2 mRNA expression and PON2 activity were lower (100% and 40%, respectively), and atorvastatin therapy increased these parameters (76% and 200%, respectively). Untreated patient HMDM incubation with atorvastatin (0 to 10 &mgr;mol/L) resulted in a dose-dependent reduction in cellular cholesterol content and in cell-mediated low-density lipoprotein (LDL) oxidation up to 79% and 66%, respectively. In parallel, PON2 mRNA expression and PON2 activity increased dose-dependently up to 3.6- and 2.1-fold, respectively. On incubation of control HMDM with acetylated-LDL or aggregated-LDL, cellular cholesterol content increased (77% and 100%), and macrophage-PON2 activity decreased (49% and 22%), respectively. In contrast, oxidized LDL increased both cellular oxidative stress and PON2 expression. Conclusions—HMDM-PON2 expression is reduced in patients with hypercholesterolemia as a result of their increased cellular cholesterol content. Atorvastatin therapy reduced both macrophage oxidative stress and cholesterol content, and upregulated PON2 expression, thus contributing to attenuation of foam cells formation.