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Increased superoxide anion production by platelets in hypercholesterolemic patients.
Thrombosis and Haemostasis 2002 May
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 sex-matched 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 an increased O2- production, which was significantly inhibited by AACOCF3 (-78%) and DPI (-56%).
CONCLUSIONS: LDL cholesterol increases platelet O2- production by activating PLA2 and NADH/NADPH enzymes. Inhibition of platelet 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.
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 sex-matched 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 an increased O2- production, which was significantly inhibited by AACOCF3 (-78%) and DPI (-56%).
CONCLUSIONS: LDL cholesterol increases platelet O2- production by activating PLA2 and NADH/NADPH enzymes. Inhibition of platelet 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.
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