title: RXR Ligands Negatively Regulate Thrombosis and Hemostasis.
abstract: Platelets have been found to express intracellular nuclear receptors including the retinoid X receptors (RXRα and RXRβ). Treatment of platelets with ligands of RXR has been shown to inhibit platelet responses to ADP and thromboxane A2; however, the effects on responses to other platelet agonists and the underlying mechanism have not been fully characterized.
  
  
  
  The effect of 9-cis-retinoic acid, docosahexaenoic acid and methoprene acid on collagen receptor (glycoprotein VI [GPVI]) agonists and thrombin-stimulated platelet function; including aggregation, granule secretion, integrin activation, calcium mobilization, integrin αIIbβ3 outside-in signaling and thrombus formation in vitro and in vivo were determined. Treatment of platelets with RXR ligands resulted in attenuation of platelet functional responses after stimulation by GPVI agonists or thrombin and inhibition of integrin αIIbβ3 outside-in signaling. Treatment with 9-cis-retinoic acid caused inhibition of thrombus formation in vitro and an impairment of thrombosis and hemostasis in vivo. Both RXR ligands stimulated protein kinase A activation, measured by VASP S157 phosphorylation, that was found to be dependent on both cAMP and nuclear factor κ-light-chain-enhancer of activated B cell activity.
  
  
  
  This study identifies a widespread, negative regulatory role for RXR in the regulation of platelet functional responses and thrombus formation and describes novel events that lead to the upregulation of protein kinase A, a known negative regulator of many aspects of platelet function. This mechanism may offer a possible explanation for the cardioprotective effects described in vivo after treatment with RXR ligands.
authors.affiliation: From the Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, United Kingdom.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Unsworth
authors.affiliation: From the Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, United Kingdom.
authors.forename: Gagan D
authors.initials: GD
authors.lastname: Flora
authors.affiliation: From the Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, United Kingdom.
authors.forename: Parvathy
authors.initials: P
authors.lastname: Sasikumar
authors.affiliation: From the Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, United Kingdom.
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Bye
authors.affiliation: From the Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, United Kingdom.
authors.forename: Tanya
authors.initials: T
authors.lastname: Sage
authors.affiliation: From the Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, United Kingdom.
authors.forename: Neline
authors.initials: N
authors.lastname: Kriek
authors.affiliation: From the Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, United Kingdom.
authors.forename: Marilena
authors.initials: M
authors.lastname: Crescente
authors.affiliation: From the Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, United Kingdom. j.m.gibbins@reading.ac.uk.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Gibbins
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006487:Hemostasis / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000819:agonists / Q000378:metabolism; D047488:Retinoid X Receptors / Q000819:agonists* / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects; D013917:Thrombin / Q000494:pharmacology; D013927:Thrombosis / Q000097:blood / Q000517:prevention & control*; D013997:Time Factors; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D005343:Fibrinolytic Agents; D008024:Ligands; D008840:Microfilament Proteins; D016328:NF-kappa B; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D047488:Retinoid X Receptors; C098341:platelet membrane glycoprotein VI; D000098662:Vasodilator-Stimulated Phosphoprotein; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D013917:Thrombin
keywords: atherosclerosis; eczema; platelet activation; thrombin