Abstract
Aspirin prevents thrombosis by inhibiting platelet cyclooxygenase (COX)-1 activity and the production of thromboxane (Tx)A2, a pro-thrombotic eicosanoid. However, the non-platelet actions of aspirin limit its antithrombotic effects. Here, we used platelet-COX-1-ko mice to define the platelet and non-platelet eicosanoids affected by aspirin. Mass-spectrometry analysis demonstrated blood from platelet-COX-1-ko and global-COX-1-ko mice produced similar eicosanoid profiles in vitro: for example, formation of TxA2, prostaglandin (PG) F2α, 11-hydroxyeicosatraenoic acid (HETE), and 15-HETE was absent in both platelet- and global-COX-1-ko mice. Conversely, in vivo, platelet-COX-1-ko mice had a distinctly different profile from global-COX-1-ko or aspirin-treated control mice, notably significantly higher levels of PGI2 metabolite. Ingenuity Pathway Analysis (IPA) predicted that platelet-COX-1-ko mice would be protected from thrombosis, forming less pro-thrombotic TxA2 and PGE2. Conversely, aspirin or lack of systemic COX-1 activity decreased the synthesis of anti-aggregatory PGI2 and PGD2 at non-platelet sites leading to predicted thrombosis increase. In vitro and in vivo thrombosis studies proved these predictions. Overall, we have established the eicosanoid profiles linked to inhibition of COX-1 in platelets and in the remainder of the cardiovascular system and linked them to anti- and pro-thrombotic effects of aspirin. These results explain why increasing aspirin dosage or aspirin addition to other drugs may lessen antithrombotic protection.
Highlights
Cardiovascular diseases are the leading cause of death and disability worldwide.[1]
We described that aspirin affects different networks of arachidonic acid (AA)-derived eicosanoids dependent upon its action on platelet COX-1 or on non-platelet COX targets
By interrogating Ingenuity Pathway Analysis (IPA), we found that loss of COX-1-related eicosanoids in platelets is antithrombotic, but loss of COX-1- and, possibly, COX-2-related eicosanoids in the remaining of the cardiovascular system limits aspirin’s antithrombotic effects
Summary
British Heart Foundation, Grant/Award Number: PG/15/79/31777, FS/16/1/31699 and PG/17/40/33028; Action Medical Research, Grant/Award Number: GN2272; National Institute of Environmental Health Sciences, Grant/Award Number: ES025034; Phelps Family Foundation and the Crump Family Foundation
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