Profiling the eicosanoid networks that underlie the anti- and pro-thrombotic effects of aspirin
2020
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: e.g. formation of TxA2, prostaglandin (PG) F2, 11-
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 predicted that platelet-COX-1-ko
mice would be protected from thrombosis, forming less prothrombotic 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 anti-thrombotic
protection.
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