Frédéric Perros1, Benoît Ranchoux2, Mohamed Izikki3, Sana Bentebbal3, Chris Happé4, Fabrice Antigny2, Philippe Jourdon2, Peter Dorfmüller5, Florence Lecerf2, Elie Fadel6, Gerald Simonneau2, Marc Humbert2, Harm Jan Bogaard4, Saadia Eddahibi3. 1. 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. 2. 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. 3. Inserm U1046, Université Montpellier, Montpellier, France. 4. Department of Pulmonary Medicine, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands. 5. 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. 6. Service de Chirurgie Thoracique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
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. OBJECTIVES: 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.
BACKGROUND: Endothelial cell (EC) dysfunction plays a central role in the pathogenesis of pulmonary arterial hypertension (PAH), promoting vasoconstriction, smooth muscle proliferation, and inflammation. OBJECTIVES: 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: Anna Klinke; Torben Schubert; Marion Müller; Ekaterina Legchenko; Jason G E Zelt; Tsukasa Shimauchi; L Christian Napp; Alexander M K Rothman; Sébastien Bonnet; Duncan J Stewart; Georg Hansmann; Volker Rudolph Journal: Cardiovasc Diagn Ther Date: 2020-10
Authors: Samar Farha; Didem Saygin; Margaret M Park; Hoi I Cheong; Kewal Asosingh; Suzy Aa Comhair; Olivia R Stephens; Emir C Roach; Jacqueline Sharp; Kristin B Highland; Frank P DiFilippo; Donald R Neumann; W H Wilson Tang; Serpil C Erzurum Journal: JCI Insight Date: 2017-08-17
Authors: Sudakshina Ghosh; Manveen Gupta; Weiling Xu; Deloris A Mavrakis; Allison J Janocha; Suzy A A Comhair; Mohammad Mahfuzul Haque; Dennis J Stuehr; Jun Yu; Peter Polgar; Sathyamangla V Naga Prasad; Serpil C Erzurum Journal: Am J Physiol Lung Cell Mol Physiol Date: 2016-04-29 Impact factor: 5.464