on October 30, 2003
Published online before print October 30, 2003, doi: 10.1161/01.ATV.0000104011.88939.06
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Submitted on August 28, 2003
Accepted on September 25, 2003
Decreased Macrophage Paraoxonase 2 Expression in Patients With Hypercholesterolemia Is the Result of Their Increased Cellular Cholesterol Content: Effect of Atorvastatin Therapy
Mira Rosenblat ;
From the Lipid Research Laboratory, Technion Faculty of Medicine (R.M., H.T., H.K., A.M.), The Rappaport Family Institute for Research in the Medical Sciences and Rambam Medical Center, and the Internal Medicine Department (H.T., H.K.), Rambam Medical Center, Haifa, Israel.
* To whom correspondence should be addressed. E-mail: aviram{at}tx.technion.ac.il.
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 ten patients with hypercholesterolema who received 20-mg/d atorvastatin participated in the study. The patients’ versus controls’ HMDM demonstrated increased cholesterol content (370%) and oxidative stress (30% to 45%). Atorvastatin therapy reduced these parameters (25% to 59%). 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 µmol/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 contributes to attenuation of foam cells formation.
Key words: Paraoxonase • oxidative stress • macrophages • cholesterol • atorvastatin
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