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 &bgr;-adrenergic receptor signaling impairs inotropic reserve. The implications of right ventricular (RV) adrenergic remodeling for inotrope selection and the therapeutic benefit of interrupting G&bgr;&ggr;–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 &bgr;1-, &agr;1- 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). &bgr;1-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 G&bgr;&ggr;–GRK2 interactions has therapeutic benefit in RVH.

[1]  X. Jeunemaître,et al.  Association Between 2 Angiographic Subtypes of Renal Artery Fibromuscular Dysplasia and Clinical Characteristics , 2012, Circulation.

[2]  Y. Okada,et al.  Neutrophil-Derived Matrix Metalloproteinase 9 Triggers Acute Aortic Dissection , 2012, Circulation.

[3]  V. V. van Hinsbergh,et al.  Effective Treatment of Edema and Endothelial Barrier Dysfunction With Imatinib , 2012, Circulation.

[4]  F. Blanco,et al.  Oxysterol-Induced Soluble Endoglin Release and Its Involvement in Hypertension , 2012, Circulation.

[5]  Changjin Lee,et al.  Exosomes Mediate the Cytoprotective Action of Mesenchymal Stromal Cells on Hypoxia-Induced Pulmonary Hypertension , 2012, Circulation.

[6]  G. Glazko,et al.  Ribosomal Protein L17, RpL17, is an Inhibitor of Vascular Smooth Muscle Growth and Carotid Intima Formation , 2012, Circulation.

[7]  P. Garred,et al.  Endogenous and Natural Complement Inhibitor Attenuates Myocardial Injury and Arterial Thrombogenesis , 2012, Circulation.

[8]  R. Karas,et al.  Rapid Estrogen Receptor Signaling Is Essential for the Protective Effects of Estrogen Against Vascular Injury , 2012, Circulation.

[9]  M. Totzeck,et al.  Dietary Nitrate Supplementation Improves Revascularization in Chronic Ischemia , 2012, Circulation.

[10]  J. Cogan,et al.  Role of BMPR2 Alternative Splicing in Heritable Pulmonary Arterial Hypertension Penetrance , 2012, Circulation.

[11]  A. Lusis,et al.  Effect of 9p21.3 Coronary Artery Disease Locus Neighboring Genes on Atherosclerosis in Mice , 2012, Circulation.

[12]  M. Hellmich,et al.  Conditional Targeting of Tumor Necrosis Factor Receptor–Associated Factor 6 Reveals Opposing Functions of Toll-Like Receptor Signaling in Endothelial and Myeloid Cells in a Mouse Model of Atherosclerosis , 2012, Circulation.

[13]  P. Ongusaha,et al.  Rho-Associated Coiled-Coil-Containing Kinase 2 Deficiency in Bone Marrow–Derived Cells Leads to Increased Cholesterol Efflux and Decreased Atherosclerosis , 2012, Circulation.

[14]  J. Douketis,et al.  Periprocedural Heparin Bridging in Patients Receiving Vitamin K Antagonists: Systematic Review and Meta-Analysis of Bleeding and Thromboembolic Rates , 2012, Circulation.

[15]  P. Tipping,et al.  Cytokine Therapy With Interleukin-2/Anti–Interleukin-2 Monoclonal Antibody Complexes Expands CD4+CD25+Foxp3+ Regulatory T Cells and Attenuates Development and Progression of Atherosclerosis , 2012, Circulation.

[16]  Takafumi Sakamoto,et al.  Bionic Baroreceptor Corrects Postural Hypotension in Rats With Impaired Baroreceptor , 2012, Circulation.

[17]  J. McClure,et al.  Activity of the Estrogen-Metabolizing Enzyme Cytochrome P450 1B1 Influences the Development of Pulmonary Arterial Hypertension , 2012, Circulation.

[18]  Des C. Jones,et al.  Impaired Natural Killer Cell Phenotype and Function in Idiopathic and Heritable Pulmonary Arterial Hypertension , 2012, Circulation.

[19]  T. Lehtimäki,et al.  Toll-Like Receptor 7 Protects From Atherosclerosis by Constraining “Inflammatory” Macrophage Activation , 2012, Circulation.

[20]  J. Loscalzo,et al.  Aldosterone Inactivates the Endothelin-B Receptor via a Cysteinyl Thiol Redox Switch to Decrease Pulmonary Endothelial Nitric Oxide Levels and Modulate Pulmonary Arterial Hypertension , 2012, Circulation.

[21]  G. Fong,et al.  Elevated Vascular Endothelial Growth Factor Receptor-2 Abundance Contributes to Increased Angiogenesis in Vascular Endothelial Growth Factor Receptor-1–Deficient Mice , 2012, Circulation.

[22]  A. Nakashima,et al.  Hyperbilirubinemia, Augmentation of Endothelial Function, and Decrease in Oxidative Stress in Gilbert Syndrome , 2012, Circulation.

[23]  Albert Hofman,et al.  Nucleotide Excision DNA Repair Is Associated With Age-Related Vascular Dysfunction , 2012, Circulation.

[24]  S. Yusuf,et al.  Periprocedural Bleeding and Thromboembolic Events With Dabigatran Compared With Warfarin: Results From the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Randomized Trial , 2012, Circulation.

[25]  D. H. Cox,et al.  Suppression of Arterial Thrombosis Without Affecting Hemostatic Parameters With a Cell-Penetrating PAR1 Pepducin , 2012, Circulation.

[26]  Kelly E. Duncan,et al.  Controlled Exposure of Healthy Young Volunteers to Ozone Causes Cardiovascular Effects , 2012, Circulation.

[27]  S. Basili,et al.  Immediate Antioxidant and Antiplatelet Effect of Atorvastatin via Inhibition of Nox2 , 2012, Circulation.

[28]  A. Xu,et al.  Cyclin-Dependent Kinase 5–Mediated Hyperphosphorylation of Sirtuin-1 Contributes to the Development of Endothelial Senescence and Atherosclerosis , 2012, Circulation.

[29]  T. McKinsey,et al.  Histone Deacetylation Inhibition in Pulmonary Hypertension: Therapeutic Potential of Valproic Acid and Suberoylanilide Hydroxamic Acid , 2012, Circulation.

[30]  A. Ahluwalia,et al.  Dietary Nitrate Ameliorates Pulmonary Hypertension: Cytoprotective Role for Endothelial Nitric Oxide Synthase and Xanthine Oxidoreductase , 2012, Circulation.

[31]  R. Collins,et al.  Lipids and Lipoproteins and Risk of Different Vascular Events in the MRC/BHF Heart Protection Study , 2012, Circulation.

[32]  Chris I. Jones,et al.  Gap Junctions and Connexin Hemichannels Underpin Hemostasis and Thrombosis , 2012, Circulation.

[33]  F. Mach,et al.  Antiplatelet Drug Response Status Does Not Predict Recurrent Ischemic Events in Stable Cardiovascular Patients: Results of the Antiplatelet Drug Resistances and Ischemic Events Study , 2012, Circulation.

[34]  M. Humbert,et al.  Résultats tardifs de la commissurotomie mitrale percutanée à 20 ans Création et validation d ’ un score de risque prédisant les résultats fonctionnels à long terme à partir d ’ une série de 912 patients , 2012 .

[35]  H. Palevsky,et al.  Validation of 6-Minute Walk Distance as a Surrogate End Point in Pulmonary Arterial Hypertension Trials , 2012, Circulation.

[36]  C. Sartori,et al.  Systemic and Pulmonary Vascular Dysfunction in Children Conceived by Assisted Reproductive Technologies , 2012, Circulation.

[37]  V. Beral,et al.  Body Mass Index, Surgery, and Risk of Venous Thromboembolism in Middle-Aged Women: A Cohort Study , 2012, Circulation.

[38]  L. Hsiao,et al.  Vascular Klotho Deficiency Potentiates the Development of Human Artery Calcification and Mediates Resistance to Fibroblast Growth Factor 23 , 2012, Circulation.

[39]  M. Daemen,et al.  Auto-Antigenic Protein-DNA Complexes Stimulate Plasmacytoid Dendritic Cells to Promote Atherosclerosis , 2012, Circulation.

[40]  T. Chavakis,et al.  Developmental Endothelial Locus-1 (Del-1) Mediates Clearance of Platelet Microparticles by the Endothelium , 2012, Circulation.

[41]  C. Thuillez,et al.  Epoxyeicosatrienoic Acids Contribute With Altered Nitric Oxide and Endothelin-1 Pathways to Conduit Artery Endothelial Dysfunction in Essential Hypertension , 2012, Circulation.

[42]  M. Leonard,et al.  Gremlin Plays a Key Role in the Pathogenesis of Pulmonary Hypertension , 2012, Circulation.

[43]  P. Wells,et al.  Development of a Clinical Prediction Rule for Risk Stratification of Recurrent Venous Thromboembolism in Patients With Cancer-Associated Venous Thromboembolism , 2010, Circulation.

[44]  P. Libby,et al.  Effects of Interleukin-1 Inhibition With Canakinumab on Hemoglobin A 1 c , Lipids , C-Reactive Protein , Interleukin-6 , and Fibrinogen A Phase IIb Randomized , Placebo-Controlled Trial , 2012 .

[45]  C. Stief,et al.  α1‐adrenoceptor activation induces phosphorylation of β2‐adrenoceptors in human prostate tissue , 2011, BJU international.

[46]  R. Gainetdinov,et al.  The Physiology, Signaling, and Pharmacology of Dopamine Receptors , 2011, Pharmacological Reviews.

[47]  V. Jeevanandam,et al.  G Protein-coupled Receptor Kinase-2 Is a Novel Regulator of Collagen Synthesis in Adult Human Cardiac Fibroblasts* , 2011, The Journal of Biological Chemistry.

[48]  A. Zaiman,et al.  Outcomes of hospitalisation for right heart failure in pulmonary arterial hypertension , 2011, European Respiratory Journal.

[49]  I. Haber,et al.  Validation of high-resolution echocardiography and magnetic resonance imaging vs. high-fidelity catheterization in experimental pulmonary hypertension. , 2010, American journal of physiology. Lung cellular and molecular physiology.

[50]  G. Vorobiof,et al.  Small Molecule Disruption of G&bgr;&ggr; Signaling Inhibits the Progression of Heart Failure , 2010, Circulation research.

[51]  M. Mancone,et al.  Dopamine receptor subtypes in the native human heart , 2010, Heart and Vessels.

[52]  C. Warnes,et al.  Adult congenital heart disease importance of the right ventricle. , 2009, Journal of the American College of Cardiology.

[53]  C. Long,et al.  Chronic Pulmonary Artery Pressure Elevation Is Insufficient to Explain Right Heart Failure , 2009, Circulation.

[54]  I. Haber,et al.  The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricle , 2009, Journal of Molecular Medicine.

[55]  Hongzhu Li,et al.  Effect of dopamine receptor 1 on apoptosis of cultured neonatal rat cardiomyocytes in simulated ischaemia/reperfusion. , 2008, Basic & clinical pharmacology & toxicology.

[56]  M. Gladwin,et al.  Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure. , 2006, Circulation.

[57]  菱田 仁,et al.  88)造影MRI delayed enhance画像による心臓サルコイドーシスの検討(第127回日本循環器学会東海地方会) , 2006 .

[58]  H. Tan,et al.  Sequence of echocardiographic changes during development of right ventricular failure in rat. , 2006, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[59]  J. Krishnan,et al.  Clinical differences between idiopathic and scleroderma-related pulmonary hypertension. , 2006, Arthritis and rheumatism.

[60]  A. Yao,et al.  Upregulated neurohumoral factors are associated with left ventricular remodeling and poor prognosis in rats with monocrotaline-induced pulmonary arterial hypertension. , 2006, Circulation journal : official journal of the Japanese Circulation Society.

[61]  D. Webb,et al.  Clinical Trials of Endothelin Antagonists in Heart Failure: A Question of Dose? , 2006, Experimental biology and medicine.

[62]  D. Lachance,et al.  Dobutamine stress echocardiography in healthy adult male rats , 2005, Cardiovascular ultrasound.

[63]  M. Lokhandwala,et al.  Rosiglitazone restores renal D1A receptor-Gs protein coupling by reducing receptor hyperphosphorylation in obese rats. , 2005, American journal of physiology. Renal physiology.

[64]  K. Leineweber,et al.  Ventricular Hypertrophy Plus Neurohumoral Activation Is Necessary to Alter the Cardiac &bgr;-Adrenoceptor System in Experimental Heart Failure , 2002, Circulation research.

[65]  Robert J. Lefkowitz,et al.  Seven-transmembrane-spanning receptors and heart function , 2002, Nature.

[66]  Robert J. Lefkowitz,et al.  Activation and targeting of extracellular signal-regulated kinases by β-arrestin scaffolds , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[67]  F. Mayor,et al.  Agonist-dependent modulation of G protein-coupled receptor kinase 2 by mitogen-activated protein kinases. , 2000, Molecular pharmacology.

[68]  R. Lefkowitz,et al.  Bbeta-adrenergic receptor kinase-1 levels in catecholamine-induced myocardial hypertrophy: regulation by beta- but not alpha1-adrenergic stimulation. , 1999, Hypertension.

[69]  R. Lefkowitz,et al.  β-Adrenergic Receptor Kinase-1 Levels in Catecholamine-Induced Myocardial Hypertrophy Regulation by β- but not α1-Adrenergic Stimulation , 1999 .

[70]  F. Harrell,et al.  A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: The Flolan International Randomized Survival Trial (FIRST). , 1997, American heart journal.

[71]  S. Rich,et al.  Neurohormonal activation in patients with right ventricular failure from pulmonary hypertension: relation to hemodynamic variables and endothelin levels. , 1995, Journal of the American College of Cardiology.

[72]  M. Böhm,et al.  Altered expression of beta-adrenergic receptor kinase and beta 1-adrenergic receptors in the failing human heart. , 1993, Circulation.

[73]  L. Mestroni,et al.  Beta-adrenergic neuroeffector abnormalities in the failing human heart are produced by local rather than systemic mechanisms. , 1992, The Journal of clinical investigation.

[74]  S. Morioka,et al.  Biventricular down-regulation of beta-adrenergic receptors in right ventricular hypertrophy induced by monocrotaline. , 1991, Japanese circulation journal.

[75]  C. Liang,et al.  Alterations in cardiac β-adrenoceptor responsiveness and adenylate cyclase system by congestive heart failure in dogs , 1987 .

[76]  C. Liang,et al.  Alterations in cardiac beta-adrenoceptor responsiveness and adenylate cyclase system by congestive heart failure in dogs. , 1987, European journal of pharmacology.

[77]  F. Douglas,et al.  Selective antagonism of the hypotensive effects of dopamine agonists in spontaneously hypertensive rats. , 1986, Hypertension.

[78]  D. Harrison,et al.  Comparison of dobutamine and dopamine in treatment of severe heart failure. , 1977, British heart journal.

[79]  S. Shaughnessy,et al.  Do No Harm: Health Systems’ Duty to Promote Clinician Well-Being , 2022, American Journal of Hospital Medicine.