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

Paul K Hamilton , Sinead Mt Hughes , Richard D Plumb , Adrian Devine , William Leahey , Kristopher S Lyons (1) , Dennis Johnston , Gary E Mcveigh

1 Therapeutics and Pharmacology

Aims: In addition to lowering cholesterol, statins may alter endothelial release of the vasodilator nitric oxide and harmful superoxide free radical. Statins also reduce cholesterol intermediates including isoprenoids. These are important for post-translational modification of substances including the GTPases Rho and Rac. By altering membrane association of these molecules, statins affect intra-cellular positioning and hence activity of a multitude of substances. These include endothelial nitric oxide synthase which produces nitric oxide (inhibited by Rho) and the nicotinamide dinucleotide (phosphate) oxidase which produces superoxide (dependent on Rac). Statins may improve endothelial function by enhancing production of nitric oxide while decreasing superoxide production. Methods: 40 hypercholesterolaemic patients were randomised to treatment with atorvastatin or placebo. 20 normolipidaemic patients were also studied. Platelet nitrite, nitric oxide and superoxide were examined as was cellular distribution of the GTPases Rho and Rac at baseline and after eight weeks of treatment. Results: Following atorvastatin therapy platelet nitric oxide was increased (3.2 pmol/ 108 platelets) and superoxide output attenuated (-3.4pmol/min/108 platelets) when compared with placebo. The detection of both Rho and Rac was significantly reduced in the membranes of platelets implying reduced activity. Conclusion: This study shows altered nitric oxide/superoxide production following statin therapy. A potential mechanism for this is the change in distribution of intracellular GTPases which was felt to be secondary to decreases in isoprenoid intermediates, suggesting that activity of the former had been affected by atorvastatin.

Mots clés: Medicine

Paul K Hamilton, Sinead Mt Hughes, Richard D Plumb, Adrian Devine, William Leahey, et al.. Statins have beneficial effects on platelet free radical activity and intracellular distribution of GTPases in hyperlipidaemia. Clinical Science, 2009, 118 (5), pp.359-366. ⟨10.1042/CS20090388⟩. ⟨hal-00541675⟩