Premium
Activation of metabolite receptor GPR91 promotes platelet aggregation and transcellular biosynthesis of leukotriene C 4
Author(s) -
Tang Xiao,
Fuchs David,
Tan Shuai,
Trauelsen Mette,
Schwartz Thue W.,
Wheelock Craig E.,
Li Nailin,
Haeggström Jesper Z.
Publication year - 2020
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.14734
Subject(s) - platelet activation , chemistry , platelet , lipid signaling , arachidonic acid , biochemistry , thromboxane a2 , phospholipase a2 , leukotriene , pharmacology , microbiology and biotechnology , receptor , biology , immunology , enzyme , asthma
Background Succinate is a Krebs cycle intermediate whose formation is enhanced under metabolic stress, and for which a selective sensor GPR91 has been identified on various cell types including platelets. Platelet‐derived eicosanoids play pivotal roles in platelet activation/aggregation, which is key to thrombus formation and progression of atherothrombosis. Objectives This study aims to decipher the molecular mechanism(s) and potential involvement of eicosanoids in succinate enhanced platelet activation/aggregation. Methods We used liquid chromatography‐mass spectrometry (LC‐MS)/MS‐based lipid mediator profiling to identify eicosanoids regulated by succinate. We ran light transmittance aggregometry and flow cytometry to assess platelet aggregation, P‐selectin expression, and platelet‐polymorphonuclear leukocyte (PMN) adherence. Various pharmacological tools were used to assess the contributions of GPR91 signalling and eicosanoids in platelet aggregation. Results Succinate and two types of synthetic non‐metabolite GPR91 agonists— cis ‐epoxysuccinate (cES) and Cmpd131—potentiated platelet aggregation, which was partially blocked by a selective GPR91 antagonist XT1. GPR91 activation increased production of 12‐hydroxy‐eicosatetraenoic acid (12‐HETE), thromboxane (TX) A 2 , and 12‐hydroxy‐heptadecatrienoic acid (12‐HHT) in human platelets, associated with phosphorylation of cytosolic phospholipase A 2 (cPLA 2 ), suggesting increased availability of free arachidonic acid. Blocking 12‐HETE and TXA 2 synthesis, or antagonism of the TXA 2 receptor, significantly reduced platelet aggregation enhanced by GPR91 signalling. Moreover, platelet‐PMN suspensions challenged with succinate exhibited enhanced transcellular biosynthesis of leukotriene C 4 (LTC 4 ), a powerful proinflammatory vascular spasmogen. Conclusion Succinate signals through GPR91 to promote biosynthesis of eicosanoids, which contribute to platelet aggregation/activation and potentially vascular inflammation. Hence, GPR91 may be a suitable target for pharmacological intervention in atherothrombotic conditions.