ArticleCirculation2012
GRK2-mediated inhibition of adrenergic and dopaminergic signaling in right ventricular hypertrophy: therapeutic implications in pulmonary hypertension.
Article in Circulation, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers, 2 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
60 citing papers in PubMed, 2 syntheses or guidelines pooled it, 120 citations in OpenAlex.
- Assessment of Right Ventricular Function in the Research Setting: Knowledge Gaps and Pathways Forward. An Official American Thoracic Society Research Statement.American journal of respiratory and critical care medicine · 2018Guideline
- An official American Thoracic Society Statement: pulmonary hypertension phenotypes.American journal of respiratory and critical care medicine · 2014Guideline
- Effectiveness of spironolactone plus ambrisentan for treatment of pulmonary arterial hypertension (from the [ARIES] study 1 and 2 trials).The American journal of cardiology · 2013Trial
- Combatting sepsis-induced myocardial dysfunction: emerging mechanisms and immunomodulatory breakthroughs.Frontiers in immunology · 2025Review
- Article
- GRK2 mediates cisplatin-induced acute liver injury via the modulation of NOX4.Cell biology and toxicology · 2024Article
- Cardiac Arrhythmias in Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: Mechanistic Insights, Pathophysiology, and Outcomes.Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc · 2024Review
- The selective serotonin reuptake inhibitor paroxetine improves right ventricular systolic function in experimental pulmonary hypertension.Journal of molecular and cellular cardiology plus · 2024Article
- Pulmonary hypertension.Nature reviews. Disease primers · 2024Review
- Pulmonary Hypertension and Right Ventricle: A Pathophysiological Insight.Clinical Medicine Insights. Cardiology · 2024Review
- Therapeutic Approaches in Pulmonary Arterial Hypertension with Beneficial Effects on Right Ventricular Function-Preclinical Studies.International journal of molecular sciences · 2023Review
- Pressure Overload and Right Ventricular Failure: From Pathophysiology to Treatment.Journal of clinical medicine · 2023Review
- Role of Dopamine in the Heart in Health and Disease.International journal of molecular sciences · 2023Review
- An updated review of experimental rodent models of pulmonary hypertension and left heart disease.Frontiers in pharmacology · 2023Review
- Exploring the failing right ventricle in pulmonary hypertension by cardiac magnetic resonance: An in vivo study utilizing Macitentan.Pulmonary circulation · 2022Article
- An integrated proteomic and transcriptomic signature of the failing right ventricle in monocrotaline induced pulmonary arterial hypertension in male rats.Frontiers in physiology · 2022Article
- Right ventricular phenotype, function, and failure: a journey from evolution to clinics.Heart failure reviews · 2021Review
- Pediatric Pulmonary Hypertension: Definitions, Mechanisms, Diagnosis, and Treatment.Comprehensive Physiology · 2021Article
- Novel Experimental Therapies for Treatment of Pulmonary Arterial Hypertension.Journal of experimental pharmacology · 2021Review
- Emerging therapies for right ventricular dysfunction and failure.Cardiovascular diagnosis and therapy · 2020Review
Corrections and comments
- Commented on by
Authors and funding
12 authors at 1 institution in 1 country.
Funding
Abstract
backgroundThe 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
resultsChamber-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.
conclusionsGRK2-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.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.