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

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...

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Veröffentlicht in:The FASEB journal 2020-08, Vol.34 (8), p.10027-10040
Hauptverfasser: 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., Gaston‐Massuet, Carles, Cottrell, Graeme S., Mitchell, Jane A., Zeldin, Darryl C., Herschman, Harvey R., Warner, Timothy D.
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container_end_page 10040
container_issue 8
container_start_page 10027
container_title The FASEB journal
container_volume 34
creator 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.
Gaston‐Massuet, Carles
Cottrell, Graeme S.
Mitchell, Jane A.
Zeldin, Darryl C.
Herschman, Harvey R.
Warner, Timothy D.
description 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.
doi_str_mv 10.1096/fj.202000312R
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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. 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subjects Animals
antithrombotic therapy
Arachidonic Acid - administration & dosage
aspirin
Aspirin - pharmacology
Blood Platelets - drug effects
Blood Platelets - metabolism
Cyclooxygenase 1 - physiology
Cyclooxygenase Inhibitors - pharmacology
eicosanoid profiling
Eicosanoids - metabolism
endothelium
Female
Male
Membrane Proteins - physiology
Mice
Mice, Inbred C57BL
Mice, Knockout
platelets
Thrombosis - drug therapy
Thrombosis - metabolism
Thrombosis - pathology
title Profiling the eicosanoid networks that underlie the anti‐ and pro‐thrombotic effects of aspirin
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