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GRK2-mediated inhibition of adrenergic and dopaminergic signaling in right ventricular hypertrophy: therapeutic implications in pulmonary hypertension.

Authors: Piao, Lin  Fang, Yong-Hu  Parikh, Kishan S  Ryan, John J  D'Souza, Karen M  Theccanat, Tiju  Toth, Peter T  Pogoriler, Jennifer  Paul, Jonathan  Blaxall, Burns C  Akhter, Shahab A  Archer, Stephen L 
Citation: Piao L, etal., Circulation. 2012 Dec 11;126(24):2859-69. doi: 10.1161/CIRCULATIONAHA.112.109868. Epub 2012 Nov 2.
Pubmed: (View Article at PubMed) PMID:23124027
DOI: Full-text: DOI:10.1161/CIRCULATIONAHA.112.109868


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 ß-adrenergic receptor signaling impairs inotropic reserve. The implications of right ventricular (RV) adrenergic remodeling for inotrope selection and the therapeutic benefit of interrupting Gßγ-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 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 ß1-, 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). ß1-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 Gßγ-GRK2 interactions has therapeutic benefit in RVH.

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CRRD Object Information
CRRD ID: 13792786
Created: 2018-09-28
Species: All species
Last Modified: 2018-09-28
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.