GRK2-Mediated Inhibition of Adrenergic and Dopaminergic Signaling in Right Ventricular Hypertrophy

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. 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-down-regulation 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.

Distinct loading conditions reveal various patterns of right ventricular adaptation

“…This might have led to a consistent overestimation of the cardiac output and, thus, of ventricular volumes. However, the observed ventricular volumes in this study are in line with previous reports (21,39). Moreover, the concomitant use of relative increases in volumes (which is not affected by this overestimation) discarded this potential limitation.…”

Animal Models of Chronic Right Ventricular Stress and Failure

“…16 ) and found that 6 weeks of pressure overload resulted in enhanced baseline RV contractility while LV baseline contractility remained unaffected. These data are different from the data published by Piao et al [ 19 ]. Piao, Archer, and collaborators showed that 4 weeks after PAB, the CO and treadmill distance were signifi cantly reduced in the PAB versus control animals.…”

The Need to Recognize the Pulmonary Circulation and the Right Ventricle as an Integrated Functional Unit: Facts and Hypotheses (2013 Grover Conference series)

“…Bogaard et al 18 demonstrated that treatment with the nonselective adrenergic blocker carvedilol improved maladaptive RVH functionally and histologically without affecting the lung circulation, and similar effects have been demonstrated utilizing other adrenergic receptor blockers. 19 More recently, Piao et al 12 evaluated the role of adrenergic desensitization in RVF and demonstrated that G protein-coupled receptor kinase 2 mediated an uncoupling of β-adrenergic receptor signaling, therefore impairing inotropic reserve. A particularly interesting finding from this study is that, at least in rats, downregulation of the β1, α1, and dopamine 1 receptors was partially independent of pressure overload.…”