title: Atorvastatin delays murine platelet activation in vivo even in the absence of endothelial NO synthase.
abstract: OBJECTIVE
  Statins decrease mortality in patients with vascular disorders, and evidence for the pleiotropic effects of statins is accumulating. Statins enhance endothelial NO synthase (eNOS) expression, thereby attenuating platelet activation and thrombus formation. Our goal was to determine whether statins have eNOS-independent effects on platelet activation.
  
  
  RESULTS
  Wild-type and eNOS-deficient mice were given a 14-day course of oral atorvastatin, and platelet activation was evaluated in vitro and in vivo. Whereas in wild-type mice atorvastatin inhibited platelet activation in vitro in response to numerous agonists, in eNOS-deficient mice, atorvastatin inhibited only thrombin-induced and protease-activated receptor 4 agonist peptide-induced platelet activation. Consistent with an eNOS-independent effect, atorvastatin inhibited platelet activation in vivo in both wild-type and eNOS-deficient mice.
  
  
  CONCLUSIONS
  Atorvastatin inhibits platelet activation via eNOS-dependent and eNOS-independent mechanisms with the latter restricted to protease-activated receptor 4-induced activation downstream to the receptor.
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, 237 Barton St East, Hamilton, Ontario, L8L 2X2 Canada.
authors.forename: Ran
authors.initials: R
authors.lastname: Ni
authors.forename: Tal
authors.initials: T
authors.lastname: Peleg
authors.forename: Peter L
authors.initials: PL
authors.lastname: Gross
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000069059:Atorvastatin; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency* / Q000235:genetics; D019007:P-Selectin / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D010979:Platelet Function Tests; D040201:Platelet Membrane Glycoprotein IIb / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D018179:Receptors, Thrombin / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013917:Thrombin / Q000378:metabolism; D013997:Time Factors
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D040201:Platelet Membrane Glycoprotein IIb; D011758:Pyrroles; D018179:Receptors, Thrombin; D000069059:Atorvastatin; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D013917:Thrombin; D006152:Cyclic GMP; C112908:protease-activated receptor 4