Fabrice Antigny1, Aurélie Hautefort2, Jolyane Meloche2, Milia Belacel-Ouari2, Boris Manoury2, Catherine Rucker-Martin2, Christine Péchoux2, François Potus2, Valérie Nadeau2, Eve Tremblay2, Grégoire Ruffenach2, Alice Bourgeois2, Peter Dorfmüller2, Sandra Breuils-Bonnet2, Elie Fadel2, Benoît Ranchoux2, Philippe Jourdon2, Barbara Girerd2, David Montani2, Steeve Provencher2, Sébastien Bonnet2, Gérald Simonneau2, Marc Humbert2, Frédéric Perros2. 1. From Université Paris-Sud, Faculté de Médecine, Kremlin-Bicêtre, France (F.A., A.H., C.R.-M., P.D., E.F., B.R., P.J., B.G., D.M., G.S., M.H., F.P.); AP-HP, Centre de Référence de l'Hypertension Pulmonaire Sévère, Département Hospitalo-Universitaire Thorax Innovation, Service de Pneumologie et Réanimation Respiratoire, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France (F.A., A.H., C.R.-M., P.D., E.F., B.R., P.J., B.G., D.M., G.S., M.H., F. Perros); UMRS 999, INSERM and Université Paris-Sud, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France (F.A., A.H., C.R.-M., P.D., E.F., B.R., P.J., B.G., D.M., G.S., M.H., F. Perros); Inserm, UMR S1180, Faculté de Pharmacie, Université Paris Sud, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique, Département Hospitalo-Universitaire TORINO, Châtenay-Malabry, France (M.B.-O., B.M.); Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec, QC, Canada (J.M., F. Potus, V.N., E.T., G.R., A.B., S.B.-B., S.P., S.B., F. Perros); INRA, UMR1313 Génétique Animale Biologie Intégrative, Equipe Plateforme MET-MIMA2-78352 Jouy-en-Josas, France (C.P.); and Service de Chirurgie Thoracique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France (E.F.). fabrice.antigny@u-psud.fr. 2. From Université Paris-Sud, Faculté de Médecine, Kremlin-Bicêtre, France (F.A., A.H., C.R.-M., P.D., E.F., B.R., P.J., B.G., D.M., G.S., M.H., F.P.); AP-HP, Centre de Référence de l'Hypertension Pulmonaire Sévère, Département Hospitalo-Universitaire Thorax Innovation, Service de Pneumologie et Réanimation Respiratoire, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France (F.A., A.H., C.R.-M., P.D., E.F., B.R., P.J., B.G., D.M., G.S., M.H., F. Perros); UMRS 999, INSERM and Université Paris-Sud, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France (F.A., A.H., C.R.-M., P.D., E.F., B.R., P.J., B.G., D.M., G.S., M.H., F. Perros); Inserm, UMR S1180, Faculté de Pharmacie, Université Paris Sud, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique, Département Hospitalo-Universitaire TORINO, Châtenay-Malabry, France (M.B.-O., B.M.); Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec, QC, Canada (J.M., F. Potus, V.N., E.T., G.R., A.B., S.B.-B., S.P., S.B., F. Perros); INRA, UMR1313 Génétique Animale Biologie Intégrative, Equipe Plateforme MET-MIMA2-78352 Jouy-en-Josas, France (C.P.); and Service de Chirurgie Thoracique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France (E.F.).
Abstract
BACKGROUND: Mutations in the KCNK3 gene have been identified in some patients suffering from heritable pulmonary arterial hypertension (PAH). KCNK3 encodes an outward rectifier K(+) channel, and each identified mutation leads to a loss of function. However, the pathophysiological role of potassium channel subfamily K member 3 (KCNK3) in PAH is unclear. We hypothesized that loss of function of KCNK3 is a hallmark of idiopathic and heritable PAH and contributes to dysfunction of pulmonary artery smooth muscle cells and pulmonary artery endothelial cells, leading to pulmonary artery remodeling: consequently, restoring KCNK3 function could alleviate experimental pulmonary hypertension (PH). METHODS AND RESULTS: We demonstrated that KCNK3 expression and function were reduced in human PAH and in monocrotaline-induced PH in rats. Using a patch-clamp technique in freshly isolated (not cultured) pulmonary artery smooth muscle cells and pulmonary artery endothelial cells, we found that KCNK3 current decreased progressively during the development of monocrotaline-induced PH and correlated with plasma-membrane depolarization. We demonstrated that KCNK3 modulated pulmonary arterial tone. Long-term inhibition of KCNK3 in rats induced distal neomuscularization and early hemodynamic signs of PH, which were related to exaggerated proliferation of pulmonary artery endothelial cells, pulmonary artery smooth muscle cell, adventitial fibroblasts, and pulmonary and systemic inflammation. Lastly, in vivo pharmacological activation of KCNK3 significantly reversed monocrotaline-induced PH in rats. CONCLUSIONS: In PAH and experimental PH, KCNK3 expression and activity are strongly reduced in pulmonary artery smooth muscle cells and endothelial cells. KCNK3 inhibition promoted increased proliferation, vasoconstriction, and inflammation. In vivo pharmacological activation of KCNK3 alleviated monocrotaline-induced PH, thus demonstrating that loss of KCNK3 is a key event in PAH pathogenesis and thus could be therapeutically targeted.
BACKGROUND: Mutations in the KCNK3 gene have been identified in some patients suffering from heritable pulmonary arterial hypertension (PAH). KCNK3 encodes an outward rectifier K(+) channel, and each identified mutation leads to a loss of function. However, the pathophysiological role of potassium channel subfamily K member 3 (KCNK3) in PAH is unclear. We hypothesized that loss of function of KCNK3 is a hallmark of idiopathic and heritable PAH and contributes to dysfunction of pulmonary artery smooth muscle cells and pulmonary artery endothelial cells, leading to pulmonary artery remodeling: consequently, restoring KCNK3 function could alleviate experimental pulmonary hypertension (PH). METHODS AND RESULTS: We demonstrated that KCNK3 expression and function were reduced in human PAH and in monocrotaline-induced PH in rats. Using a patch-clamp technique in freshly isolated (not cultured) pulmonary artery smooth muscle cells and pulmonary artery endothelial cells, we found that KCNK3 current decreased progressively during the development of monocrotaline-induced PH and correlated with plasma-membrane depolarization. We demonstrated that KCNK3 modulated pulmonary arterial tone. Long-term inhibition of KCNK3 in rats induced distal neomuscularization and early hemodynamic signs of PH, which were related to exaggerated proliferation of pulmonary artery endothelial cells, pulmonary artery smooth muscle cell, adventitial fibroblasts, and pulmonary and systemic inflammation. Lastly, in vivo pharmacological activation of KCNK3 significantly reversed monocrotaline-induced PH in rats. CONCLUSIONS: In PAH and experimental PH, KCNK3 expression and activity are strongly reduced in pulmonary artery smooth muscle cells and endothelial cells. KCNK3 inhibition promoted increased proliferation, vasoconstriction, and inflammation. In vivo pharmacological activation of KCNK3 alleviated monocrotaline-induced PH, thus demonstrating that loss of KCNK3 is a key event in PAH pathogenesis and thus could be therapeutically targeted.
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