Atorvastatin Delays Murine Platelet Activation In Vivo Even in the Absence of Endothelial NO Synthase

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. METHODS AND 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.