title: Statins have beneficial effects on platelet free  radical activity and intracellular distribution  of GTPases in hyperlipidaemia.
abstract: In addition to lowering cholesterol, statins may alter endothelial release of the vasodilator NO and harmful superoxide free radicals. Statins also reduce cholesterol intermediates including isoprenoids. These are important for post-translational modification of substances including the GTPases Rho and Rac. By altering the membrane association of these molecules, statins affect intracellular positioning and hence activity of a multitude of substances. These include eNOS(endothelial NO synthase), which produces NO (inhibited by Rho), and NADPH oxidase, which produces superoxide (dependent on Rac). Statins may improve endothelial function by enhancing production of NO while decreasing superoxide production. A total of 40 hypercholesterolaemic patients were randomized to treatment with either atorvastatin or placebo; 20 normolipidaemic patients were also studied. Platelet nitrite, NO and superoxide were examined as was the cellular distribution of the GTPases Rho and Rac at baseline and after 8 weeks of treatment.Following atorvastatin therapy, platelet NO was increased (3.2 pmol/10(8) platelets) and superoxide output was attenuated [-3.4 pmol min(-1) (10(8) platelets)(-1)] when compared with placebo. The detection of both Rho and Rac was significantly reduced in the membranes of platelets, implying reduced activity. In conclusion, the results of the present study show altered NO/superoxide production following statin therapy. A potential mechanism for this is the change in the distribution of intracellular GTPases, which was considered to be secondary to decreases in isoprenoid intermediates, suggesting that the activity of the former had been affected by atorvastatin.
authors.affiliation: Department of Therapeutics and Pharmacology, Queens University, Whitla Medical Building, Lisburn Road, Belfast, BT9 7BL, UK.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Hamilton
authors.forename: Sinead M T
authors.initials: SM
authors.lastname: Hughes
authors.forename: Richard D
authors.initials: RD
authors.lastname: Plumb
authors.forename: Adrian
authors.initials: A
authors.lastname: Devine
authors.forename: William
authors.initials: W
authors.lastname: Leahey
authors.forename: Kristopher S
authors.initials: KS
authors.lastname: Lyons
authors.forename: Dennis
authors.initials: D
authors.lastname: Johnston
authors.forename: Gary E
authors.initials: GE
authors.lastname: McVeigh
mesh_terms: D000328:Adult; D000368:Aged; D000069059:Atorvastatin; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D004311:Double-Blind Method; D005609:Free Radicals / Q000097:blood*; D020558:GTP Phosphohydrolases / Q000097:blood*; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006949:Hyperlipidemias / Q000097:blood* / Q000188:drug therapy; D008875:Middle Aged; D009569:Nitric Oxide / Q000096:biosynthesis / Q000097:blood; D011758:Pyrroles / Q000494:pharmacology*; D013481:Superoxides / Q000097:blood; D020744:rac GTP-Binding Proteins / Q000097:blood; D020741:rho GTP-Binding Proteins / Q000097:blood
chemical_list: D005609:Free Radicals; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D013481:Superoxides; D009569:Nitric Oxide; D000069059:Atorvastatin; D020558:GTP Phosphohydrolases; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins