Increased superoxide anion production by platelets in hypercholesterolemic patients.
OBJECTIVE
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.
Sanguigni
Valerio
V
Department of Internal Medicine, University Tor Vergata, Rome, Italy.
Pignatelli
Pasquale
P
Caccese
Daniela
D
Pulcinelli
Fabio M
FM
Lenti
Luisa
L
Magnaterra
Roberta
R
Martini
Francesca
F
Lauro
Renato
R
Violi
Francesco
F
D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use; D016718:Arachidonic Acid / Q000097:blood; D000069059:Atorvastatin; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood / Q000494:pharmacology; D003430:Cross-Sectional Studies; D005260:Female; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood* / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D013481:Superoxides / Q000097:blood*; D014280:Triglycerides / Q000097:blood
D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D011758:Pyrroles; D014280:Triglycerides; D013481:Superoxides; D016718:Arachidonic Acid; D002784:Cholesterol; D000069059:Atorvastatin