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

Publication ,  Journal Article
Piao, L; Fang, Y-H; Parikh, KS; Ryan, JJ; D'Souza, KM; Theccanat, T; Toth, PT; Pogoriler, J; Paul, J; Blaxall, BC; Akhter, SA; Archer, SL
Published in: Circulation
December 11, 2012

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. 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 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.

Duke Scholars

Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

December 11, 2012

Volume

126

Issue

24

Start / End Page

2859 / 2869

Location

United States

Related Subject Headings

  • Xanthenes
  • Signal Transduction
  • Receptors, Dopamine D1
  • Receptors, Adrenergic, beta
  • Rats, Sprague-Dawley
  • Rats
  • Oligonucleotide Array Sequence Analysis
  • Myocytes, Cardiac
  • Myocardial Contraction
  • Male
 

Citation

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MLA
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Piao, L., Fang, Y.-H., Parikh, K. S., Ryan, J. J., D’Souza, K. M., Theccanat, T., … Archer, S. L. (2012). GRK2-mediated inhibition of adrenergic and dopaminergic signaling in right ventricular hypertrophy: therapeutic implications in pulmonary hypertension. Circulation, 126(24), 2859–2869. https://doi.org/10.1161/CIRCULATIONAHA.112.109868
Piao, Lin, Yong-Hu Fang, Kishan S. Parikh, John J. Ryan, Karen M. D’Souza, Tiju Theccanat, Peter T. Toth, et al. “GRK2-mediated inhibition of adrenergic and dopaminergic signaling in right ventricular hypertrophy: therapeutic implications in pulmonary hypertension.Circulation 126, no. 24 (December 11, 2012): 2859–69. https://doi.org/10.1161/CIRCULATIONAHA.112.109868.
Piao L, Fang Y-H, Parikh KS, Ryan JJ, D’Souza KM, Theccanat T, et al. GRK2-mediated inhibition of adrenergic and dopaminergic signaling in right ventricular hypertrophy: therapeutic implications in pulmonary hypertension. Circulation. 2012 Dec 11;126(24):2859–69.
Piao, Lin, et al. “GRK2-mediated inhibition of adrenergic and dopaminergic signaling in right ventricular hypertrophy: therapeutic implications in pulmonary hypertension.Circulation, vol. 126, no. 24, Dec. 2012, pp. 2859–69. Pubmed, doi:10.1161/CIRCULATIONAHA.112.109868.
Piao L, Fang Y-H, Parikh KS, Ryan JJ, D’Souza KM, Theccanat T, Toth PT, Pogoriler J, Paul J, Blaxall BC, Akhter SA, Archer SL. GRK2-mediated inhibition of adrenergic and dopaminergic signaling in right ventricular hypertrophy: therapeutic implications in pulmonary hypertension. Circulation. 2012 Dec 11;126(24):2859–2869.

Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

December 11, 2012

Volume

126

Issue

24

Start / End Page

2859 / 2869

Location

United States

Related Subject Headings

  • Xanthenes
  • Signal Transduction
  • Receptors, Dopamine D1
  • Receptors, Adrenergic, beta
  • Rats, Sprague-Dawley
  • Rats
  • Oligonucleotide Array Sequence Analysis
  • Myocytes, Cardiac
  • Myocardial Contraction
  • Male