Increased Superoxide Anion Production by Platelets in Hypercholesterolemic Patients

Summary

Objectives

The purpose of this study was to investigate the relationship between hypercholesterolemia and superoxide anion production.

Background

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.

Methods

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.

Results

O₂ ⁻ platelet generation was significantly higher (p <0.001) and significantly related to LDL cholesterol (p < 0.001 ) in patients as compared to controls. 8-week treatment with 10 mg/day atorvastatin significantly reduced both LDL cholesterol and O₂ ⁻ 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.

Condensed Abstract

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.

Keywords

Hypercholesterolemia - arachidonic acid - platelets - superoxide anion - atorvastatin

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