Phospholipid-esterified eicosanoids are generated in agonist-activated human platelets and enhance tissue factor-dependent thrombin generation

Thomas, Christopher P. ORCID: https://orcid.org/0000-0001-5840-8613, Morgan, Lloyd T., Maskrey, Ben, Murphy, Robert C., Kuhn, Hartmut, Hazen, Stanley L., Goodall, Alison H., Hamali, Hassan A., Collins, Peter William ORCID: https://orcid.org/0000-0002-6410-1324 and O'Donnell, Valerie Bridget ORCID: https://orcid.org/0000-0003-4089-8460 2010. Phospholipid-esterified eicosanoids are generated in agonist-activated human platelets and enhance tissue factor-dependent thrombin generation. Journal of Biological Chemistry 285 (10) , pp. 6891-6903. 10.1074/jbc.M109.078428

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Abstract

Here, a group of specific lipids, comprising phosphatidylethanolamine (PE)- or phosphatidylcholine (PC)-esterified 12S-hydroxyeicosatetraenoic acid (12S-HETE), generated by 12-lipoxygenase was identified and characterized. 12S-HETE-PE/PCs were formed within 5 min of activation by thrombin, ionophore, or collagen. Esterified HETE levels generated in response to thrombin were 5.85 ± 1.42 (PE) or 18.35 ± 4.61 (PC), whereas free was 65.5 ± 17.6 ng/4 × 107 cells (n = 5 separate donors, mean ± S.E.). Their generation was stimulated by triggering protease-activated receptors-1 and -4 and signaling via Ca2+ mobilization secretory phospholipase A2, platelet-activating factor-acetylhydrolase, src tyrosine kinases, and protein kinase C. Stable isotope labeling showed that they form predominantly by esterification that occurs on the same time scale as free acid generation. Unlike free 12S-HETE that is secreted, esterified HETEs remain cell-associated, with HETE-PEs migrating to the outside of the plasma membrane. 12-Lipoxygenase inhibition attenuated externalization of native PE and phosphatidylserine and HETE-PEs. Platelets from a patient with the bleeding disorder, Scott syndrome, did not externalize HETE-PEs, and liposomes supplemented with HETE-PC dose-dependently enhanced tissue factor-dependent thrombin generation in vitro. This suggests a role for these novel lipids in promoting coagulation. Thus, oxidized phospholipids form by receptor/agonist mechanisms, not merely as an undesirable consequence of vascular and inflammatory disease.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > R Medicine (General)
Uncontrolled Keywords:	Eicosanoids; Eicosanoids/Arachidonic Acid; Eicosanoids/Function; Eicosanoids/Lipoxygenase Pathway; Lipid; Lipid/Phospholipid
Publisher:	American Society for Biochemistry and Molecular Biology
ISSN:	0021-9258
Last Modified:	19 Oct 2022 10:44
URI:	https://orca.cardiff.ac.uk/id/eprint/25388

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