title: Rosuvastatin reduces platelet recruitment by inhibiting NADPH oxidase activation.
abstract: Rosuvastatin increased vascular endothelial NO and attenuated platelet activation after ischemia-reperfusion in mice; nevertheless, the influence of rosuvastatin on the activation of human platelets and the underlying mechanism has never been investigated. In an in vitro study platelets from 8 healthy donors were incubated with scalar concentrations of rosuvastatin (1-10 μM) before activation. Platelet recruitment (PR), that mimics the propagation of platelet aggregation and is dependent upon isoprostane formation, was investigated. PR was inhibited by rosuvastatin in concentration-dependent manner concomitantly with down-regulation of platelet release of the pro-thrombotic molecule CD40L. This effect was associated with lower production of platelet reactive oxygen species (ROS), isoprostane and activation of the glycoprotein IIb/IIIa and was counteracted by exogenous addition of isoprostanes. Conversely, rosuvastatin concentration-dependently increased platelet NO. Platelet isoprostane formation mainly depends from NADPH oxidase. Rosuvastatin concentration-dependently inhibited platelet sNOX2-dp release, a specific marker of NADPH oxidase activation, PKC phosphorylation and p47(phox) translocation from cytosol to membranes. In an ex vivo study 10 hypercolesterolemic patients were randomly allocated to diet or rosuvastatin (20 mg). We observed that as early as 2h after rosuvastatin PR, platelet isoprostanes formation, platelet CD40L and sNOX2-dp decreased while platelet NO increased; no changes were detected in diet-assigned patients. This study shows that in vitro rosuvastatin impairs platelet activation via inhibition of NOX2-derived oxidative stress. This effect, which is associated ex vivo with acute inhibition of platelet activation, suggests that rosuvastatin behaves as an antiplatelet drug.
authors.affiliation: Prima Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Italy. pasquale.pignatelli@uniroma1.it
authors.forename: Pasquale
authors.initials: P
authors.lastname: Pignatelli
authors.forename: Roberto
authors.initials: R
authors.lastname: Carnevale
authors.forename: Serena
authors.initials: S
authors.lastname: Di Santo
authors.forename: Simona
authors.initials: S
authors.lastname: Bartimoccia
authors.forename: Cristina
authors.initials: C
authors.lastname: Nocella
authors.forename: Tommasa
authors.initials: T
authors.lastname: Vicario
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Loffredo
authors.forename: Francesco
authors.initials: F
authors.lastname: Angelico
authors.forename: Francesco
authors.initials: F
authors.lastname: Violi
mesh_terms: D000328:Adult; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D005464:Fluorobenzenes / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D019255:NADPH Oxidases / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D011743:Pyrimidines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D009569:Nitric Oxide; D000068718:Rosuvastatin Calcium; D019255:NADPH Oxidases