Profiling the eicosanoid networks that underlie the anti- and pro-thrombotic effects of aspirin.
FASEB J
; 34(8): 10027-10040, 2020 08.
Article
em En
| MEDLINE
| ID: mdl-32592197
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Trombose
/
Plaquetas
/
Eicosanoides
/
Aspirina
/
Inibidores de Ciclo-Oxigenase
/
Ciclo-Oxigenase 1
/
Proteínas de Membrana
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article