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. Objectives: 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 A(2) (TXA(2)) synthesis; b) the additive effect of statins on TXA(2) synthesis in platelets treated with a submaximally effective concentration of aspirin and c) the biochemical mechanisms involved. Methods and Results: Washed human platelets were incubated with statins (1-20 mu M), and stimulated with collagen (1 mu g/ml) or arachidonic acid (AA) (200 mu M) 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 (1 mu M) 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/TXA(2) synthase activities. Atorvastatin and simvastatin concentration-dependently inhibited the collagen-induced increase in cytosolic calcium and the kinetics of cPLA(2) phosphorylation. Lipophilic statins reduced phosphorylation of both ERK1/2 and p38MAPK, which regulate cPLA(2) phosphorylation and calcium movement. Conclusion: We report for the first time a direct downregulation by atorvastatin and simvastatin of platelet cPLA(2) activity through effects on calcium and MAPK, which reduce collagen-induced TXA(2) synthesis. These mechanisms might contribute to their beneficial effects, even in aspirin-treated patients. (C) 2013 Elsevier Ltd. All rights reserved.