Reduction of platelet cytosolic phospholipase A2 activity by atorvastatin and simvastatin: biochemical regulatory mechanisms.
Statins have demonstrated effects beyond reducing cholesterol level that may contribute to their clinical benefit, including effects on platelet biochemistry and function.


OBJECTIVE
To explore and compare the antiplatelet effect of two lipophilic statins (atorvastatin and simvastatin) and one hydrophilic statin (pravastatin) concerning: a) collagen-induced platelet aggregation and thromboxane A2 (TXA2) synthesis; b) the additive effect of statins on TXA2 synthesis in platelets treated with a submaximally effective concentration of aspirin and c) the biochemical mechanisms involved.


RESULTS
Washed human platelets were incubated with statins (1-20μM), and stimulated with collagen (1μg/ml) or arachidonic acid (AA) (200μM) and TXB2 was quantified by ELISA. Incubation with simvastatin or atorvastatin reduced (36.2% and 31.0%, respectively) collagen-induced TXB2 synthesis (p<0.05) and platelet aggregation (p<0.001), whereas pravastatin had no effects. Simultaneous incubation with a submaximally effective concentration of aspirin (1μM) and atorvastatin or simvastatin significantly increased the inhibition of TXB2 synthesis by aspirin by 4.4- and 4.1-fold, respectively. Statins did not affect AA-induced TXB2 synthesis, excluding an effect on COX-1/TXA2 synthase activities. Atorvastatin and simvastatin concentration-dependently inhibited the collagen-induced increase in cytosolic calcium and the kinetics of cPLA2 phosphorylation. Lipophilic statins reduced phosphorylation of both ERK1/2 and p38 MAPK, which regulate cPLA2 phosphorylation and calcium movement.


CONCLUSIONS
We report for the first time a direct downregulation by atorvastatin and simvastatin of platelet cPLA2 activity through effects on calcium and MAPK, which reduce collagen-induced TXA2 synthesis. These mechanisms might contribute to their beneficial effects, even in aspirin-treated patients.
Research Center, University Hospital La Fe, Valencia, Spain. moscardo_ant@gva.es
Antonio
A
Moscardó
Juana
J
Vallés
Ana
A
Latorre
Isabel
I
Madrid
María Teresa
MT
Santos
D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D000069059:Atorvastatin; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology*; D002118:Calcium / Q000097:blood; D003094:Collagen / Q000494:pharmacology; D051545:Cyclooxygenase 1 / Q000097:blood; D004338:Drug Combinations; D004357:Drug Synergism; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000097:blood; D064801:Phospholipase A2 Inhibitors / Q000494:pharmacology*; D054467:Phospholipases A2 / Q000097:blood*; D010766:Phosphorylation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D017035:Pravastatin / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D019821:Simvastatin / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000096:biosynthesis* / Q000097:blood; D013930:Thromboxane-A Synthase / Q000097:blood
D000924:Anticholesteremic Agents; D004338:Drug Combinations; D006538:Heptanoic Acids; D064801:Phospholipase A2 Inhibitors; D011758:Pyrroles; D013928:Thromboxane A2; D003094:Collagen; D000069059:Atorvastatin; D019821:Simvastatin; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D020928:Mitogen-Activated Protein Kinases; D054467:Phospholipases A2; D013930:Thromboxane-A Synthase; D017035:Pravastatin; D001241:Aspirin; D002118:Calcium