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    Profiling the eicosanoid networks that underlie the anti- and pro-thrombotic effects of aspirin.

    Crescente, Marilena ORCID logoORCID: https://orcid.org/0000-0003-3164-512X, Armstrong, Paul C, Kirkby, Nicholas S, Edin, Matthew L, Chan, Melissa V, Lih, Fred B, Jiao, Jing, Maffucci, Tania, Allan, Harriet E, Mein, Charles A, Gaston-Massuet, Carles, Cottrell, Graeme S, Mitchell, Jane A, Zeldin, Darryl C, Herschman, Harvey R and Warner, Timothy D (2020) Profiling the eicosanoid networks that underlie the anti- and pro-thrombotic effects of aspirin. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 34 (8). pp. 10027-10040. ISSN 0892-6638

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    Aspirin prevents thrombosis by inhibiting platelet cyclooxygenase (COX)-1 activity and the production of thromboxane (Tx)A<sub>2</sub> , 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 TxA<sub>2</sub> , prostaglandin (PG) F<sub>2α</sub> , 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 PGI<sub>2</sub> metabolite. Ingenuity Pathway Analysis (IPA) predicted that platelet-COX-1-ko mice would be protected from thrombosis, forming less pro-thrombotic TxA<sub>2</sub> and PGE<sub>2</sub> . Conversely, aspirin or lack of systemic COX-1 activity decreased the synthesis of anti-aggregatory PGI<sub>2</sub> and PGD<sub>2</sub> 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.

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