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12‐HETrE Exerts its Antithrombotic Effects Through the Prostacyclin Receptor
Author(s) -
Tourdot Benjamin,
Isingizwe Zitha,
Adili Reheman,
Holman Ted,
Holinstat Michael
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.675.2
Subject(s) - antithrombotic , receptor , prostacyclin , chemistry , lysophosphatidic acid , pharmacology , agonist , biology , biochemistry , medicine
The antithrombotic effect of dihomo‐γ‐linolenic acid (DGLA), an ω‐6 fatty acid, was recently shown to be dependent upon 12‐lipoxygenase (12‐LOX) and its DGLA‐derived metabolite, 12‐hydroxy‐eicosatrienoic acid (12‐HETrE). 12‐HETrE inhibits platelet activation via the Gα s signaling pathway; however, the Gα s ‐coupled receptor by which 12‐HETrE mediates its antiplatelet effects has yet to be identified. We hypothesized that 12‐HETrE exerts its antiplatelet effects through a known lipid binding Gα s ‐coupled prostanoid receptor expressed by platelets: IP, EP 2 , EP 4 , or DP 1 . In this study, we found that pharmacological inhibition of the IP receptor reduced 12‐HETrE's antiplatelet effects in humans, while genetic ablation of the IP receptor in murine platelets completely abolished the inhibitory effects of 12‐HETrE. Consistent with our in vitro studies, 12‐HETrE's antithrombotic effects were abolished in IP receptor deficient mice. Further, ectopic expression of the IP receptor in Jurkat cells was sufficient for 12‐HETrE to induced Gα s signaling. Together this data demonstrates that 12‐HETrE's antiplatelet effects are at least partially dependent on IP receptor signaling. Importantly, this work identified a new class of endogenous IP receptor agonist that will aid in the rationale design of novel IP receptor therapeutics. Additionally, this study provides further knowledge of the mechanism by which DGLA supplementation inhibits platelets function. Support or Funding Information This work was funded in part through the National Institutes of Health grants R01 GM105671 (MH & TRH), R01 HL114405 (MH & TRH), R01 MD 007880 (MH), R01 AG047986 (MH & TRH), and F32 HL129491 (BET), as well as the University of Michigan Frankel Cardiovascular Center Summer Fellowship Program (ZRI).