Abstract Number: PB1704
Meeting: ISTH 2020 Congress
Background: Cyclooxygenase (COX) metabolism of arachidonic acid (AA) leads to the production of eicosanoids such as thromboxane (Tx)A2, prostaglandin (PG)I2 and PGE2, important for thrombosis, inflammation and cancer. However, platelets, endothelial cells and leukocytes synthesize other metabolites not comprehensively profiled.
Aims: Here, we used platelet-COX-1 knockout (KO), global-COX-1 KO and aspirin-treated control mice to determine by mass spectrometry the eicosanoid profile associated with the activity of COX-1 in platelets and of COX-1 and COX-2 in other blood cells and vasculature.
Methods: In vitro stimulation of whole blood with A23187 (50 µM) or in vivo injection of AA (2.8 mg/Kg) were used to elicit eicosanoid release. The levels of metabolites were determined by mass-spectrometry.
Results: Hierarchical analysis identified 3 different clusters of AA-derived eicosanoids produced in vitro: 1) TxA2, PGF2α, 11- hydroxyeicosatraenoic acid (HETE) and 15-HETE, that were absent in platelet-COX-1 and global-COX-1 KO mice; 2) PGD2 and PGE2, that were absent in global-COX-1 KO mice and partially reduced in platelet-COX-1 KO mice; 3) 5-HETE, 12-HETE and leukotriene B4 that were unchanged. Eicosanoids produced in vivo clustered differently in platelet-COX-1 ko mice than in global-COX-1 KO and aspirin-treated control mice. All demonstrated absence of TxA2 but, unlike global-COX-1 KO and aspirin (10 mg/Kg)-treated control mice, platelet COX-1 KO mice still produced PGI2, PGE2, PGF2α, 11-HETE and 15-HETE. From these data, Ingenuity Pathway Analysis (IPA) predicted enhanced cardiovascular protection for platelet-COX-1 KO mice, but increased thrombosis in global COX-1 KO and aspirin-treated mice. Lessened inflammation was predicted in global COX-1 KO and aspirin-treated mice, while cancer was predicted as decreased in platelet COX-1 KO mice, global COX-1 KO and aspirin-treated mice.
Conclusions: The activity of COX-1 in platelets and of COX-1 and COX-2 in other blood cells and the vasculature associate to distinct eicosanoid profiles underpinning important and different roles in cardiovascular, inflammation and cancer protection.
To cite this abstract in AMA style:Crescente M, Armstrong PC, Kirkby NS, Edin ML, Chan MV, Lih FB, Jiao J, Maffucci T, Allan HE, Mein CA, Gaston-Massuet C, Cottrell GS, Mitchell JA, Zeldin DC, Herschman HH, Warner TD. Profiling of COX-dependent Eicosanoids Produced by Blood Cells and the Vasculature [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/profiling-of-cox-dependent-eicosanoids-produced-by-blood-cells-and-the-vasculature/. Accessed October 1, 2023.
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