title: TCDD and omeprazole prime platelets through the aryl hydrocarbon receptor (AhR) non-genomic pathway.
abstract: The role of the aryl hydrocarbon receptor (AhR) in hemostasis has recently gained increased attention. Here, we demonstrate, by qRT-PCR and western blot, that human platelets express both AhR mRNA and AhR protein. AhR protein levels increase in a dose dependent manner when incubated with either 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or omeprazole. Treatment of platelets with puromycin blocks increased AhR protein synthesis in the presence of AhR activators. Additionally, treatment of platelets with either activator results in phosphorylation of p38MAPK and cPLA2, two key signaling molecules in platelet activation pathways. Using the AhR competitive inhibitors alpha naphthoflavone and CH-223191, we show that phosphorylation of p38MAPK is AhR dependent. Further, inhibition of p38MAPK blocks downstream cPLA2 phosphorylation induced by TCDD or omeprazole. Treatment with AhR activators results in platelet priming, as demonstrated by increased platelet aggregation, which is inhibited by AhR antagonists. Our data support a model of the platelet AhR non-genomic pathway in which treatment with AhR activators results in increased expression of the AhR, phosphorylation of p38MAPK and cPLA2, leading to platelet priming in response to agonist.
authors: Department of Anatomy, Physiology & Cell Biology, Davis, United States.
authors: Mónica
authors: M
authors: Pombo
authors: Department of Molecular Biosciences, Davis, United States.
authors: Michael W
authors: MW
authors: Lamé
authors: Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, United States.
authors: Naomi J
authors: NJ
authors: Walker
authors: Department of Anatomy, Physiology & Cell Biology, Davis, United States.
authors: Danh H
authors: DH
authors: Huynh
authors: Department of Anatomy, Physiology & Cell Biology, Davis, United States. Electronic address: FTablin@ucdavis.edu.
authors: Fern
authors: F
authors: Tablin
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D054513:Group IV Phospholipases A2 / Q000378:metabolism; D006801:Humans; D008024:Ligands; D009853:Omeprazole / Q000633:toxicity*; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054328:Proton Pump Inhibitors / Q000633:toxicity*; D011691:Puromycin / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018179:Receptors, Thrombin / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D054513:Group IV Phospholipases A2; D008024:Ligands; D009853:Omeprazole; D010446:Peptide Fragments; D000072317:Polychlorinated Dibenzodioxins; D047428:Protein Kinase Inhibitors; D054328:Proton Pump Inhibitors; D011691:Puromycin; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D018179:Receptors, Thrombin; D048051:p38 Mitogen-Activated Protein Kinases; C111235:AHR protein, human; C082835:thrombin receptor peptide (42-47); C516389:PLA2G4A protein, human
keywords: AhR non-genomic pathway; Platelet priming; Platelet signaling; cPLA(2); p38MAPK