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

Crescente, M., Armstrong, P. C., Kirkby, N. S., Edin, M. L., Chan, M. V., Lih, F. B., Jiao, J., Maffucci, T., Allan, H. E., Mein, C. A., Gaston-Massuet, C., Cottrell, G. S. ORCID: https://orcid.org/0000-0001-9098-7627, Mitchell, J. A., Zeldin, D. C., Herschman, H. R. and Warner, T. D. (2020) Profiling the eicosanoid networks that underlie the anti- and pro-thrombotic effects of aspirin. FASEB Journal, 34 (8). pp. 10027-10040. ISSN 0892-6638 doi: 10.1096/fj.202000312R

Abstract/Summary

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.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/90724
Identification Number/DOI	10.1096/fj.202000312R
Refereed	Yes
Divisions	Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
Publisher	Federation of American Societies for Experimental Biology
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