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.


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 micromol/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.
Rosenblat
Mira
M
Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences and Rambam Medical Center, Haifa, Israel.
Hayek
Tony
T
Hussein
Khetam
K
Aviram
Michael
M
D000328:Adult; D043303:Aryldialkylphosphatase / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D000069059:Atorvastatin; D002784:Cholesterol / Q000378:metabolism; D004790:Enzyme Induction; D005487:Foam Cells / Q000201:enzymology / Q000473:pathology; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D008264:Macrophages / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D002784:Cholesterol; D000069059:Atorvastatin; D043303:Aryldialkylphosphatase