Abstract Number: PB0398
Meeting: ISTH 2022 Congress
Background: The antiplatelet effect of polyunsaturated fatty acids is primarily attributed to its metabolism to bioactive eicosanoids by oxygenases such as lipoxygenases (LOX). Platelets have demonstrated the ability to generate 15-LOX-derived eicosanoids; however, whether 15-LOX is in the platelet and further required to the formation of its eicosanoids remain unclear.
Aims: We sought to elucidate whether 15-LOX is required for the formation of 15-LOX eicosanoids in the platelet and determine the mechanistic effects of 15(S)-hydroxyeicosatrienoic acid (15-HETrE) and 15(S)-hydroxyeicosatetraenoic (15-HETE) on platelet reactivity.
Methods: Platelet aggregation and intracellular signaling were assessed in human platelets treated with the 15-LOX eicosanoids. Leukocyte-depleted platelets were treated with inhibitors for 15-LOX-1 (ML351), 15-LOX-2 (1A1U) or 12-LOX (ML355) prior to agonist-induced aggregation. To assess 15-LOX expression in platelets, 15-LOX-1, 15-LOX-2 and 12-LOX enzymes were used as controls.
Results: Treatment with 15-HETrE or 15-HETE was shown to attenuate collagen-induced platelet aggregation (Fig 1A) due to inhibition of PKC activation (Fig 1B), calcium mobilization (Fig 1C), ⍺IIbβ3 activation (Fig 1D), and granule secretion (Fig 1E-F). While 15-HETrE was demonstrated to inhibit platelets through activation of PPARβ (Fig 2A), 15-HETE was shown to activate PPAR⍺ (Fig 2B). Although platelets treated with DGLA were shown to form 15-HETrE, treatment with 15-LOX-1 or 15-LOX-2 inhibitor did not rescue collagen-induced platelet aggregation (Fig 2C) or ATP secretion (Fig 2D). Additionally, expression of 15-LOX-1 (Fig 2E), but not 15-LOX-2 (Fig 2F), was decreased in leukocyte-depleted platelets compared to non-depleted platelets.
Conclusion(s): These findings suggest that 15-LOX eicosanoids regulate platelet activity, but are formed through a 15-LOX-independent pathway in platelets. Furthermore, since 15-LOX is highly expressed in leukocytes, it is reasonable to suggest that its regulation of platelet reactivity may involve a transcellular mechanism between platelets and leukocytes through the formation of the eicosanoids. This study aids to better understand role of 15-LOX on regulation of platelet activity.
To cite this abstract in AMA style:
Yamaguchi A, Tourdot B, Perry S, Lee G, Rhoads N, van Hoorebeke C, Sorrentino J, Yeung J, Li C, Freedman C, Holman T, Holinstat M. Fatty acids negatively regulate platelet function through formation of noncanonical 15-lipoxygenase-derived eicosanoids [abstract]. https://abstracts.isth.org/abstract/fatty-acids-negatively-regulate-platelet-function-through-formation-of-noncanonical-15-lipoxygenase-derived-eicosanoids/. Accessed March 21, 2024.« Back to ISTH 2022 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/fatty-acids-negatively-regulate-platelet-function-through-formation-of-noncanonical-15-lipoxygenase-derived-eicosanoids/