title: Rho-GTPase-dependent platelet-neutrophil interaction affected by HMG-CoA reductase inhibition with altered adenosine nucleotide release and function.
abstract: Platelet activation and aggregation is considered a crucial step in the initiation and aggravation of arterial thrombosis. ADP from activated platelets is recognized as major factor in thrombus formation and is a potent stimulator of oxygen-free radical release from neutrophils. The aim of the present investigation was to determine in vitro the direct effects of statins on ATP and ADP secretion by platelets and its impact on subsequent oxidative burst activity in neutrophils. Human neutrophils and platelets were isolated from peripheral blood. Levels of platelet-derived ATP and ADP were measured by high-performance liquid chromatography, oxygen-free radical release of neutrophils was measured fluorometrically, and chemotaxis experiments were performed. Rho-GTPases were studied by Western blot analysis. Thrombin-activated platelets primed neutrophils for enhanced oxygen-free radical release on triggering with formyl-Met-Leu-Phe, reduced by cerivastatin and simvastatin treatment of platelets. The two statins decreased the amount of adenosine-derivative release in these cells. Rho-GTPases, required for the thrombin signaling in platelets and neutrophils, were decreased after coincubation with statins. Data demonstrate that inhibition of Rho-GTPases by statins inhibit platelet ADP and ATP release and the consecutive augmentation of neutrophil oxygen-free radical release. Statins affect platelet-neutrophil interactions by altering Rho-GTPase-dependent adenosine nucleotide function.
authors.affiliation: Division of General Internal Medicine, Department of Internal Medicine, University of Innsbruck, Innsbruck, Austria.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Kaneider
authors.forename: Petra
authors.initials: P
authors.lastname: Egger
authors.forename: Stefan
authors.initials: S
authors.lastname: Dunzendorfer
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Wiedermann
mesh_terms: D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors / Q000097:blood*; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000097:blood*; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D002450:Cell Communication / Q000187:drug effects* / Q000502:physiology; D002469:Cell Separation; D002630:Chemotactic Factors / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D018375:Neutrophil Activation / Q000187:drug effects / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology; D058919:Purinergic P2 Receptor Antagonists; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000502:physiology; D016897:Respiratory Burst / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019821:Simvastatin / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology; D014343:Trypan Blue / Q000494:pharmacology; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D002630:Chemotactic Factors; D017077:Culture Media, Conditioned; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D011725:Pyridines; D017382:Reactive Oxygen Species; D018048:Receptors, Purinergic P2; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D019821:Simvastatin; C086276:cerivastatin; D013917:Thrombin; D020741:rho GTP-Binding Proteins; D014343:Trypan Blue