Increased Superoxide Anion Production by Platelets in Hypercholesterolemic Patients

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Abstract
The purpose of this study was to investigate the relationship between hypercholesterolemia and superoxide anion production. Experimental studies demonstrated that hypercholesterolemia is associated with enhanced cellular superoxide anion (O2 −) production. Aim of the study was to assess whether the same phenomenon occurs in humans. Lipid profile and platelet O2 − production were measured in 28 patients with hypercholesterolemia, compared with 25 age- and sexmatched healthy subjects, and in 21 out of the 28 patients after 8-week treatment with 10 mg/day atorvastatin (a HMGCoA reductase inhibitor). In order to assess the mechanism by which LDL cholesterol interferes with platelet production of O2 −, human platelets were incubated with LDL cholesterol in the presence of either an inhibitor of the phospholipaseA2 enzyme, AACOCF3, or an inhibitor of NADH/NADPH oxidases, DPI. O2 − platelet generation was significantly higher (p 2 − platelet production. This effect was partially related to the cholesterol-lowering, in that three days of treatment with atorvastatin significantly decreased platelet O2 − production, while no significant change in LDL-cholesterol levels was observed. Platelets incubated with LDL cholesterol showed O2 − release by atorvastatin is partially related to cholesterol lowering effect, suggesting that other mechanisms could be responsible for the antioxidant activity of the drug. Platelets O2 − production is enhanced in patients with hypercholesterolemia and significantly correlated with LDL cholesterol. Treatment of hypercholesterolemic patients with atorvastatin inhibited platelet O2 − production through a mechanism which is partially dependent on its cholesterol lowering effect, indicating a non-lipid lowering antioxidant effect. In vitro incubation of platelets with LDL cholesterol enhanced O2 − production which was inhibited by inhibitors of phospholipase A2 and NADH/NADPH enzymes, suggesting that these pathways contribute to LDL-induced platelet O2– production.