title: GRK2-mediated inhibition of adrenergic and dopaminergic signaling in right ventricular hypertrophy: therapeutic implications in pulmonary hypertension.
abstract: BACKGROUND
  The cause and consequences of impaired adrenergic signaling in right ventricular failure/hypertrophy (RVH) are poorly understood. We hypothesized that G protein-coupled receptor kinase-2 (GRK2)-mediated uncoupling of β-adrenergic receptor signaling impairs inotropic reserve. The implications of right ventricular (RV) adrenergic remodeling for inotrope selection and the therapeutic benefit of interrupting Gβγ-GRK2 interaction, using gallein, were tested.
  
  
  RESULTS
  Chamber-specificity and cellular localization of adrenergic remodeling were compared in rodent RVH associated with pulmonary arterial hypertension (PAH-RVH; SU5416+chronic-hypoxia or Monocrotaline) versus pulmonary artery banding-induced RVH (PAB-RVH). Results were corroborated in RV arrays from 10 PAH patients versus controls. Inotropic reserve was assessed in RV- and left ventricular-Langendorff models and in vivo. Gallein therapy (1.8 mg/kg/day ×2-weeks) was assessed. Despite similar RVH, cardiac output (58.3±4.9 versus 82.9±4.8 mL/min; P<0.001) and treadmill distance (41.5±11.6 versus 244.1±12.4 m; P<0.001) were lower in PAH-RVH versus PAB-RVH. In PAH-RVH versus PAB-RVH there was greater downregulation of β1-, α1- and dopamine-1 receptors, more left ventricular involvement, and greater impairment of RV contractile reserve. RV GRK2 activity increased in parallel with a reduction in both adrenergic receptor expression and inotrope-stimulated cAMP levels (P<0.01). β1-receptor downregulation also occurred in human PAH-RVH. Dobutamine was superior to dopamine as an RV inotrope, both ex vivo and in vivo.
  
  
  CONCLUSIONS
  GRK2-mediated desensitization-downregulation of adrenergic and dopaminergic receptors impairs inotropic reserve in PAH-RVH. Acute inotropic support in RVH is best accomplished by dobutamine, reflecting its better coupling to adenylyl cyclase and the reliance of dopamine on dopamine-1-receptor signaling, which is impaired in RVH. Inhibiting Gβγ-GRK2 interactions has therapeutic benefit in RVH.
authors.affiliation: Section of Cardiology, Department of Medicine, University of Chicago Medical Center, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Piao
authors.forename: Yong-Hu
authors.initials: YH
authors.lastname: Fang
authors.forename: Kishan S
authors.initials: KS
authors.lastname: Parikh
authors.forename: John J
authors.initials: JJ
authors.lastname: Ryan
authors.forename: Karen M
authors.initials: KM
authors.lastname: D'Souza
authors.forename: Tiju
authors.initials: T
authors.lastname: Theccanat
authors.forename: Peter T
authors.initials: PT
authors.lastname: Toth
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pogoriler
authors.forename: Jonathan
authors.initials: J
authors.lastname: Paul
authors.forename: Burns C
authors.initials: BC
authors.lastname: Blaxall
authors.forename: Shahab A
authors.initials: SA
authors.lastname: Akhter
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Archer
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D004280:Dobutamine / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014966:Xanthenes / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D011943:Receptors, Adrenergic, beta; D017447:Receptors, Dopamine D1; D014966:Xanthenes; D004280:Dobutamine; C007820:gallein; C496569:Grk2 protein, rat; D054769:G-Protein-Coupled Receptor Kinase 2; D004298:Dopamine