Antithrombotic properties of pravastatin reducing intra-thrombus fibrin deposition under high shear blood flow conditions.
In addition to lowering cholesterol, the 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors (statins) have a range of pleiotropic effects that help reduce the risk of adverse cardiovascular events. We sought to understand the molecular mechanisms by which statins could exert anti-platelet actions under physiologic whole blood flow conditions. Using an in vitro perfusion chamber system, we examined the anti-platelet effects of pravastatin under whole blood flow conditions with high or low shear rates. We determined that pravastatin significantly suppressed platelet activation-dependent procoagulant activity, decreasing P-selectin membrane expression, tissue factor accumulation, and thrombin binding within platelet thrombi generated on a von Willebrand factor-surface under high shear rate conditions. These effects resulted in reductions of intra-thrombus fibrin deposition. These antithrombotic properties of pravastatin, which were comparable to those of atorvastatin, could be abrogated by mevalonate. Our experimental approach revealed a novel mechanism mediating the anti-platelet action of statins. Shear rate-dependent antithrombotic activity may explain the favourable effect of pravastatin on the reduction in cardiovascular events that typically occur in vivo under whole blood flow conditions with high shear rates.
Department of Regulatory Medicine for Thrombosis, Nara Medical University 840 Shijo-cho, Kashihara, Nara 634-8521, Japan.
Masaaki
M
Hamada
Mitsuhiko
M
Sugimoto
Hideto
H
Matsui
Tomohiro
T
Mizuno
Yasuaki
Y
Shida
Masaaki
M
Doi
Hidetada
H
Fukushima
Kenji
K
Nishio
Akira
A
Yoshioka
Midori
M
Shima
D000069059:Atorvastatin; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005337:Fibrin / Q000378:metabolism*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000494:pharmacology; D019007:P-Selectin / Q000097:blood; D010477:Perfusion; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D017035:Pravastatin / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D012039:Regional Blood Flow; D013314:Stress, Mechanical; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism; D013927:Thrombosis / Q000097:blood / Q000517:prevention & control*; D013997:Time Factors; D014841:von Willebrand Factor / Q000378:metabolism
D005343:Fibrinolytic Agents; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D011758:Pyrroles; C546937:SELP protein, human; D014841:von Willebrand Factor; D005337:Fibrin; D013925:Thromboplastin; D000069059:Atorvastatin; D013917:Thrombin; D017035:Pravastatin; D008798:Mevalonic Acid