Abstract Number: PB1763
Meeting: ISTH 2020 Congress
Background: Arterial thrombosis is the underlying cause for several cardiovascular-related events, such as myocardial infarction, ischemia, and stroke. While dietary supplementation that includes polyunsaturated fatty acids (PUFAs) have been proposed to elicit a cardiovascular protective effect, several conflicting clinical trials have reported an overall inconclusive anti-thrombotic role. The underlying mechanism by which omega-6 PUFAs impart antiplatelet properties remains unknown.
Aims: The current study sought to investigate whether fatty acids produced in the body following administration of the omega-6 PUFA docosapentaenoic acid (DPA), and its oxylipin metabolites provide direct cardiovascular protection and the mechanisms mediating their antiplatelet effects.
Methods: Human and mouse blood and isolated platelets were tested with omega-6 DPA and its 12-LOX-derived oxylipins, 11-HpDPA and 14-HpDPA, in their ability to inhibit platelet activation. In human and mouse studies, pharmacological and genetic approaches were utilized to investigate and verify the underlying mechanism by which DPA and their oxylipins evoke anti-platelet effects.
Results: DPAn-6 was demonstrated to potently inhibit platelet activation through its 12-LOX-derived oxylipins, 11-HpDPAn-6 and 14-HpDPAn-6, and the inhibitory effects were selectively reversed through inhibition of PPARα. PPARα binding was confirmed using a PPARα transcription reporter assay and PPARα-deficient mice. These approaches confirmed selectivity of platelet inhibition was due to effects of 11-HpDPAn-6 and 14-HpDPAn-6 acting through PPARα. Finally, mice administered DPAn-6, 11-HpDPAn-6, or 14-HpDPAn-6 exhibited reduced thrombus formation in the arteriole following a laser-induced injury of the cremaster, while thrombus growth was not further affected by the oxylipins in the PPARα-deficient mice.
Conclusions: The current study demonstrated that DPAn-6 and its oxylipins potently and effectively inhibits platelet activation and thrombosis. Platelet function is regulated in part through and oxylipin-induced PPARα-dependent manner, suggesting targeting PPARα may represent a new strategy to treat thrombotic-related diseases.
To cite this abstract in AMA style:Yeung J, Adili R, Holman T, Holinstat M. Omega-6 DPA and its 12-LOX Oxylipins Regulate Platelet Reactivity in a Non-genomic PPARa-dependent Manner [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/omega-6-dpa-and-its-12-lox-oxylipins-regulate-platelet-reactivity-in-a-non-genomic-ppara-dependent-manner/. Accessed December 3, 2021.
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