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Profiling the eicosanoid networks that underlie the anti‐ and pro‐thrombotic effects of aspirin
Author(s) -
Crescente Marilena,
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.,
GastonMassuet Carles,
Cottrell Graeme S.,
Mitchell Jane A.,
Zeldin Darryl C.,
Herschman Harvey R.,
Warner Timothy D.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202000312r
Subject(s) - eicosanoid , aspirin , profiling (computer programming) , medicine , pharmacology , chemistry , arachidonic acid , biochemistry , computer science , enzyme , operating system
Aspirin prevents thrombosis by inhibiting platelet cyclooxygenase (COX)‐1 activity and the production of thromboxane (Tx)A 2 , 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 2 , prostaglandin (PG) F 2α , 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 2 metabolite. Ingenuity Pathway Analysis (IPA) predicted that platelet‐COX‐1‐ko mice would be protected from thrombosis, forming less pro‐thrombotic TxA 2 and PGE 2 . Conversely, aspirin or lack of systemic COX‐1 activity decreased the synthesis of anti‐aggregatory PGI 2 and PGD 2 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.