title: Glucocorticoids as modulators of expression and activity of Antithrombin (At): potential clinical relevance.
abstract: BACKGROUND
  An inverse relationship has been reported between decreased postoperative Antithrombin (AT) plasmatic levels and the incidence of complications. We hypothesized that Nuclear Hormone Receptors could modulate the expression of SERPINC1, encoding AT, through a Hormone Regulatory Element present in its promoter, and thus hormone analogs could be a pharmacological complement in surgical procedures to activate endogenous AT synthesis.
  
  
  METHODS
  The expression of SERPINC1 was analyzed in HepG2 cells by quantitative RT-PCR and Western Blot. Two studies were conducted with (a) patients submitted to cardiac surgery with cardiopulmonary bypass receiving (n =17) or not (n=321) glucocorticoids (GCs) as part of their pharmacological treatment, and (b) patients who received (n =20) or not (n=16) GCs as part of their surgery (exodontia or knee arthroscopic, respectively). AT activity in plasma was determined by Innovance Antithrombin Test on a BCS XP System hemostasis analyzer.
  
  
  RESULTS
  13 nuclear hormone receptor ligands were assayed, being GW4064 (FXR ligand) the most potent activator. Retinoids, activating RXR, and GCs (Dexamethasone, cortisone and methylprednisolone) also resulted in increased AT expression. Chronic GC treatment mitigates the decreased AT activity observed after cardiac surgery. In patients who received two acute GC doses, pre-operative and post-operative AT activity was similar, whereas a significant decrease was observed after surgery in untreated patients.
  
  
  CONCLUSIONS
  Whereas retinoids and FXR ligands are investigational compounds, regulation of AT by GCS could have a higher potential for translation to clinical practice, pre-conditioning the patient against complications related to reduced AT levels. Larger prospective studies are needed to define the exact role of GCs and their potential clinical utility in cardiac surgery.
authors.affiliation: Departamento de Patología y Terapia Molecular y Celular, Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas, C/ Jaime Roig 11, 46010 Valencia Spain.
authors.forename: Domingo
authors.initials: D
authors.lastname: Barettino
authors.affiliation: Departamento de Patología y Terapia Molecular y Celular, Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas, C/ Jaime Roig 11, 46010 Valencia Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Masiá
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Universidad de Valencia, Avda Vicent Andres Estelles s/n, 46100 Burjassot, Valencia Spain.
authors.forename: Fermí
authors.initials: F
authors.lastname: Montó
authors.affiliation: Departamento de Patología y Terapia Molecular y Celular, Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas, C/ Jaime Roig 11, 46010 Valencia Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: Pérez
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Universidad de Valencia, Avda Vicent Andres Estelles s/n, 46100 Burjassot, Valencia Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: D'Ocon
authors.affiliation: Departamento de Farmacia, Facultad de Ciencias de la Salud, Universidad CEU Cardenal Herrera, Edificio Seminario s/n 46113, Moncada, Valencia Spain.
authors.forename: Lucrecia
authors.initials: L
authors.lastname: Moreno
authors.affiliation: Departamento de Anestesiología, Cuidados Críticos y Terapéutica del Dolor, Hospital Universitario La Ribera, Avda Corbera, Km 1, 46600 Alzira, Valencia Spain. Electronic address: VMuedra@Hospital-Ribera.com.
authors.forename: Vicente
authors.initials: V
authors.lastname: Muedra
mesh_terms: D000368:Aged; D000991:Antithrombins / Q000378:metabolism*; D001483:Base Sequence; D002315:Cardiopulmonary Bypass; D015331:Cohort Studies; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008024:Ligands; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016601:RNA-Binding Proteins / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D000991:Antithrombins; C096916:FXR1 protein, human; D005938:Glucocorticoids; D007555:Isoxazoles; D008024:Ligands; D016601:RNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D047488:Retinoid X Receptors; D012176:Retinoids; C412815:GW 4064
keywords: Antithrombin; FXR; Glucocorticoids; Nuclear hormone receptors; RXR; Surgery