Clinical Science (2010) 118, 359-366 - P. K. Hamilton and others - Statins and platelet free radical activity

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Clinical Science (2010) 118, (359–366) (Printed in Great Britain)

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Statins have beneficial effects on platelet free radical activity and intracellular distribution of GTPases in hyperlipidaemia

Paul K. Hamilton, Sinead M.T. Hughes, Richard D. Plumb, Adrian Devine, William Leahey, Kristopher S. Lyons, Dennis Johnston and Gary E. McVeigh

Department of Therapeutics and Pharmacology, Queens University, Whitla Medical Building, Lisburn Road, Belfast, BT9 7BL, U.K.

Key words: GTPase, hyperlipidaemia, isoprenoid, nitric oxide, statin, platelet, superoxide radical.

Abbreviations: BMI, body mass index; BP, blood pressure; CI, confidence interval; CVD, cardiovascular disease; DPI, diphenyleneiodonium; DU, densitometry units; ED, endothelial dysfunction; eNOS, endothelial NO synthase; GGPP, geranylgeranyl pyrophosphate; HDL, high-density lipoprotein; IQR, interquartile range; LDL, low-density lipoprotein; L-NAME, N^G-nitro-L-arginine methyl ester; O₂^•−, superoxide radical; ROS, reactive oxygen species; SOD, superoxide dismutase.

Correspondence: Dr Kristopher S Lyons (email kristopherlyons@hotmail.co.uk).

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/10⁸ platelets) and superoxide output was attenuated [−3.4 pmol·min⁻¹·(10⁸ 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.