title: Nebivolol for improving endothelial dysfunction, pulmonary vascular remodeling, and right heart function in pulmonary hypertension.
abstract: BACKGROUND
  Endothelial cell (EC) dysfunction plays a central role in the pathogenesis of pulmonary arterial hypertension (PAH), promoting vasoconstriction, smooth muscle proliferation, and inflammation.
  
  
  OBJECTIVE
  This study sought to test the hypothesis that nebivolol, a β1-antagonist and β2,3-agonist, may improve PAH and reverse the PAH-related phenotype of pulmonary ECs (P-EC).
  
  
  METHODS
  We compared the effects of nebivolol with metoprolol, a first-generation β1-selective β-blocker, on human cultured PAH and control P-EC proliferation, vasoactive and proinflammatory factor production, and crosstalk with PA smooth muscle cells. We assessed the effects of both β-blockers in precontracted PA rings. We also compared the effects of both β-blockers in experimental PAH.
  
  
  RESULTS
  PAH P-ECs overexpressed the proinflammatory mediators interleukin-6 and monocyte chemoattractant protein-1, fibroblast growth factor-2, and the potent vasoconstrictive agent endothelin-1 as compared with control cells. This pathological phenotype was corrected by nebivolol but not metoprolol in a dose-dependent fashion. We confirmed that PAH P-EC proliferate more than control cells and stimulate more PA smooth muscle cell mitosis, a growth abnormality that was normalized by nebivolol but not by metoprolol. Nebivolol but not metoprolol induced endothelium-dependent and nitric oxide-dependent relaxation of PA. Nebivolol was more potent than metoprolol in improving cardiac function, pulmonary vascular remodeling, and inflammation of rats with monocrotaline-induced pulmonary hypertension.
  
  
  CONCLUSIONS
  Nebivolol could be a promising option for the management of PAH, improving endothelial dysfunction, pulmonary vascular remodeling, and right heart function. Until clinical studies are undertaken, however, routine use of β-blockers in PAH cannot be recommended.
authors: University Paris-Sud, Faculté de médecine, Kremlin-Bicêtre, France; AP-HP, DHU TORINO, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Réanimation Respiratoire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; INSERM UMR-S 999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France. Electronic address: frederic.perros@inserm.fr.
authors: Frédéric
authors: F
authors: Perros
authors: University Paris-Sud, Faculté de médecine, Kremlin-Bicêtre, France; AP-HP, DHU TORINO, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Réanimation Respiratoire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; INSERM UMR-S 999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors: Benoît
authors: B
authors: Ranchoux
authors: Inserm U1046, Université Montpellier, Montpellier, France.
authors: Mohamed
authors: M
authors: Izikki
authors: Inserm U1046, Université Montpellier, Montpellier, France.
authors: Sana
authors: S
authors: Bentebbal
authors: Department of Pulmonary Medicine, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands.
authors: Chris
authors: C
authors: Happé
authors: University Paris-Sud, Faculté de médecine, Kremlin-Bicêtre, France; AP-HP, DHU TORINO, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Réanimation Respiratoire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; INSERM UMR-S 999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors: Fabrice
authors: F
authors: Antigny
authors: University Paris-Sud, Faculté de médecine, Kremlin-Bicêtre, France; AP-HP, DHU TORINO, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Réanimation Respiratoire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; INSERM UMR-S 999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors: Philippe
authors: P
authors: Jourdon
authors: University Paris-Sud, Faculté de médecine, Kremlin-Bicêtre, France; AP-HP, DHU TORINO, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Réanimation Respiratoire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; INSERM UMR-S 999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France; Service d'Anatomie Pathologique, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors: Peter
authors: P
authors: Dorfmüller
authors: University Paris-Sud, Faculté de médecine, Kremlin-Bicêtre, France; AP-HP, DHU TORINO, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Réanimation Respiratoire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; INSERM UMR-S 999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors: Florence
authors: F
authors: Lecerf
authors: Service de Chirurgie Thoracique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors: Elie
authors: E
authors: Fadel
authors: University Paris-Sud, Faculté de médecine, Kremlin-Bicêtre, France; AP-HP, DHU TORINO, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Réanimation Respiratoire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; INSERM UMR-S 999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors: Gerald
authors: G
authors: Simonneau
authors: University Paris-Sud, Faculté de médecine, Kremlin-Bicêtre, France; AP-HP, DHU TORINO, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Réanimation Respiratoire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; INSERM UMR-S 999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
authors: Marc
authors: M
authors: Humbert
authors: Department of Pulmonary Medicine, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands.
authors: Harm Jan
authors: HJ
authors: Bogaard
authors: Inserm U1046, Université Montpellier, Montpellier, France.
authors: Saadia
authors: S
authors: Eddahibi
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology / Q000627:therapeutic use*; D002450:Cell Communication / Q000187:drug effects; D018929:Cell Culture Techniques; D049109:Cell Proliferation; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D004983:Ethanolamines / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008790:Metoprolol / Q000494:pharmacology / Q000627:therapeutic use; D016686:Monocrotaline; D032389:Myocytes, Smooth Muscle; D000068577:Nebivolol; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D066253:Vascular Remodeling / Q000187:drug effects*
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D001578:Benzopyrans; D004983:Ethanolamines; D000068577:Nebivolol; D016686:Monocrotaline; D008790:Metoprolol
keywords: endothelial dysfunction; inflammation; nebivolol; pulmonary hypertension; β-blocker