GRK2-Mediated Inhibition of Adrenergic and Dopaminergic Signaling in Right Ventricular Hypertrophy: Therapeutic Implications in Pulmonary Hypertension
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 RV adrenergic remodeling for inotrope selection and the therapeutic benefit of interrupting Gβγ-GRK2 interaction, using gallein, were tested.
Methods and 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 LV-Langendorff models and in vivo. Gallein therapy (1.8mg/Kg/Day×2-weeks) was assessed. Despite similar RVH, cardiac output (58.3±4.9 vs. 82.9±±4.8 ml/min, P<0.001) and treadmill distance (41.5±11.6 vs. 244.1±12.4m, P<0.001) were lower in PAH-RVH vs. PAB-RVH. In PAH-RVH vs PAB-RVH there was greater downregulation of β1-, α1- and dopamine1-receptors, more LV involvement and greater impairment of RV contractile reserve. RV GRK2 activity declined in parallel with reduced 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, ex vivo and in vivo. Gallein decreased GRK2 expression and improved RV function 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 dopamine's reliance on dopamine1-receptor signaling, which is impaired in RVH. Inhibiting Gβγ-GRK2 interactions has therapeutic benefit in RVH.
- β-adrenergic receptor kinase
- Gβγ signaling
- SU5416+chronic hypoxia pulmonary hypertension
- right ventricular failure
- Received April 5, 2012.
- Accepted October 15, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited