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3 results on '"MESH: Potassium Channels, Tandem Pore Domain"'

1. Kcnk3 dysfunction exaggerates the development of pulmonary hypertension induced by left ventricular pressure overload

Author

Rui Adão, Catherine Rucker-Martin, David Montani, P. Mendes-Ferreira, Mélanie Lambert, Valérie Domergue, Véronique Capuano, Rozenn Quarck, Maria-Rosa Ghigna, Frédéric Perros, Jean-Luc Vachiery, Hélène Leribeuz, Angèle Boet, Carmen Brás-Silva, Marc Humbert, Fabrice Antigny, Quarck, Rozenn, Hôpital Bicêtre, Adhésion et Inflammation (LAI), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Chirurgical Marie Lannelongue (CCML), Universidade do Porto = University of Porto, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University Hospitals Leuven [Leuven], Institut Paris Saclay d’Innovation Thérapeutique (IPSIT), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay, Cliniques Universitaires de Bruxelles [Bruxelles, Belgique], Antigny, Fabrice, and ANR-18-CE14-0023,KAPAH,KCNK3 une nouvelle cible thérapeutique dans l'hypertension artérielle pulmonaire(2018)

Subjects
MESH: Signal Transduction, 0301 basic medicine, Physiology, [SDV]Life Sciences [q-bio], Proliferation, 030204 cardiovascular system & hematology, K2P3.1, MESH: Ventricular Function, Left, Ventricular Function, Left, Muscle hypertrophy, Ventricular Dysfunction, Left, 0302 clinical medicine, Fibrosis, MESH: Ventricular Dysfunction, Left, MESH: Animals, MESH: Nerve Tissue Proteins, Pulmonary Arterial Hypertension, Ascending-aortic constriction, MESH: Potassium Channels, Tandem Pore Domain, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Ventricular pressure, Cardiology, Rats, Transgenic, Cardiology and Cardiovascular Medicine, MESH: Vascular Remodeling, Signal Transduction, MESH: Pulmonary Arterial Hypertension, medicine.medical_specialty, MESH: Mutation, MESH: Arterial Pressure, MESH: Pulmonary Artery, Concentric hypertrophy, Nerve Tissue Proteins, Pulmonary Artery, Vascular Remodeling, 03 medical and health sciences, Potassium Channels, Tandem Pore Domain, Physiology (medical), Internal medicine, medicine.artery, Ventricular Pressure, medicine, Animals, Arterial Pressure, MESH: Ventricular Pressure, Lung, business.industry, Task-1, medicine.disease, Pulmonary hypertension, PH due to left heart diseases, Disease Models, Animal, 030104 developmental biology, Ventricle, MESH: Rats, Transgenic, Mutation, Pulmonary artery, MESH: Disease Models, Animal, business
Abstract

Aims Pulmonary hypertension (PH) is a common complication of left heart disease (LHD, Group 2 PH) leading to right ventricular (RV) failure and death. Several loss-of-function (LOF) mutations in KCNK3 were identified in pulmonary arterial hypertension (PAH, Group 1 PH). Additionally, we found that KCNK3 dysfunction is a hallmark of PAH at pulmonary vascular and RV levels. However, the role of KCNK3 in the pathobiology of PH due to LHD is unknown. Methods and results We evaluated the role of KCNK3 on PH induced by ascending aortic constriction (AAC), in WT and Kcnk3-LOF-mutated rats, by echocardiography, RV catheterization, histology analyses, and molecular biology experiments. We found that Kcnk3-LOF-mutation had no consequence on the development of left ventricular (LV) compensated concentric hypertrophy in AAC, while left atrial emptying fraction was impaired in AAC-Kcnk3-mutated rats. AAC-animals (WT and Kcnk3-mutated rats) developed PH secondary to AAC and Kcnk3-mutated rats developed more severe PH than WT. AAC-Kcnk3-mutated rats developed RV and LV fibrosis in association with an increase of Col1a1 mRNA in right ventricle and left ventricle. AAC-Kcnk3-mutated rats developed severe pulmonary vascular (pulmonary artery as well as pulmonary veins) remodelling with intense peri-vascular and peri-bronchial inflammation, perivascular oedema, alveolar wall thickening, and exaggerated lung vascular cell proliferation compared to AAC-WT-rats. Finally, in lung, right ventricle, left ventricle, and left atrium of AAC-Kcnk3-mutated rats, we found a strong increased expression of Il-6 and periostin expression and a reduction of lung Ctnnd1 mRNA (coding for p120 catenin), contributing to the exaggerated pulmonary and heart remodelling and pulmonary vascular oedema in AAC-Kcnk3-mutated rats. Conclusions Our results indicate that Kcnk3-LOF is a key event in the pathobiology of PH due to AAC, suggesting that Kcnk3 channel dysfunction could play a potential key role in the development of PH due to LHD.

Published
2021
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2. Proteomic Analysis of KCNK3 Loss of Expression Identified Dysregulated Pathways in Pulmonary Vascular Cells

Author

Le Ribeuz, Hélène, Dumont, Florent, Ruellou, Guillaume, Lambert, Mélanie, Balliau, Thierry, Quatredeniers, Marceau, Girerd, Barbara, Cohen-Kaminsky, Sylvia, Mercier, Olaf, Yen-Nicolaÿ, Stéphanie, Humbert, Marc, Montani, David, Capuano, Véronique, Antigny, Fabrice, Faculté de Médecine Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Ingénierie et Plateformes au Service de l'Innovation Thérapeutique (IPSIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Génétique Quantitative et Evolution - Le Moulon (Génétique Végétale) (GQE-Le Moulon), AgroParisTech-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM, Université Paris-Saclay, Marie Lannelongue Hospital, Therapeutic Innovation Doctoral School (ED569), Région Ile de France (convention n◦ EX024607), ANR-18-CE14-0023,KAPAH,KCNK3 une nouvelle cible thérapeutique dans l'hypertension artérielle pulmonaire(2018), Adhésion et Inflammation (LAI), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Chirurgical Marie Lannelongue (CCML), Hôpital Bicêtre, Plateforme d'Analyse Protéomique de Paris Sud Ouest (PAPPSO), AgroParisTech, and Antigny, Fabrice

Subjects
Proteomics, MESH: Signal Transduction, Proteome, [SDV]Life Sciences [q-bio], Myocytes, Smooth Muscle, MESH: Pulmonary Artery, Nerve Tissue Proteins, MESH: Molecular Sequence Annotation, Pulmonary Artery, Article, lcsh:Chemistry, Potassium Channels, Tandem Pore Domain, Humans, MESH: Endothelial Cells, MESH: Nerve Tissue Proteins, lcsh:QH301-705.5, Cells, Cultured, proteomic, MESH: Humans, MESH: Proteomics, Computational Biology, Endothelial Cells, MESH: Potassium Channels, Tandem Pore Domain, Molecular Sequence Annotation, MESH: Myocytes, Smooth Muscle, PAH, MESH: Gene Knockdown Techniques, MESH: Gene Expression Regulation, [SDV] Life Sciences [q-bio], MESH: Proteome, Gene Expression Regulation, lcsh:Biology (General), lcsh:QD1-999, Gene Knockdown Techniques, MESH: Biomarkers, Biomarkers, Signal Transduction, MESH: Cells, Cultured, MESH: Computational Biology, potassium channel
Abstract

International audience; The physiopathology of pulmonary arterial hypertension (PAH) is characterized by pulmonary artery smooth muscle cell (PASMC) and endothelial cell (PAEC) dysfunction, contributing to pulmonary arterial obstruction and PAH progression. KCNK3 loss of function mutations are responsible for the first channelopathy identified in PAH. Loss of KCNK3 function/expression is a hallmark of PAH. However, the molecular mechanisms involved in KCNK3 dysfunction are mostly unknown. To identify the pathological molecular mechanisms downstream of KCNK3 in human PASMCs (hPASMCs) and human PAECs (hPAECs), we used a Liquid Chromatography-Tandem Mass Spectrometry-based proteomic approach to identify the molecular pathways regulated by KCNK3. KCNK3 loss of expression was induced in control hPASMCs or hPAECs by specific siRNA targeting KCNK3. We found that the loss of KCNK3 expression in hPAECs and hPASMCs leads to 326 and 222 proteins differentially expressed, respectively. Among them, 53 proteins were common to hPAECs and hPASMCs. The specific proteome remodeling in hPAECs in absence of KCNK3 was mostly related to the activation of glycolysis, the superpathway of methionine degradation, and the mTOR signaling pathways, and to a reduction in EIF2 signaling pathways. In hPASMCs, we found an activation of the PI3K/AKT signaling pathways and a reduction in EIF2 signaling and the Purine Nucleotides De Novo Biosynthesis II and IL-8 signaling pathways. Common to hPAECs and hPASMCs, we found that the loss of KCNK3 expression leads to the activation of the NRF2-mediated oxidative stress response and a reduction in the interferon pathway. In the hPAECs and hPASMCs, we found an increased expression of HO-1 (heme oxygenase-1) and a decreased IFIT3 (interferon-induced proteins with tetratricopeptide repeats 3) (confirmed by Western blotting), allowing us to identify these axes to understand the consequences of KCNK3 dysfunction. Our experiments, based on the loss of KCNK3 expression by a specific siRNA strategy in control hPAECs and hPASMCs, allow us to identify differences in the activation of several signaling pathways, indicating the key role played by KCNK3 dysfunction in the development of PAH. Altogether, these results allow us to better understand the consequences of KCNK3 dysfunction and suggest that KCNK3 loss of expression acts in favor of the proliferation and migration of hPASMCs and promotes the metabolic shift and apoptosis resistance of hPAECs.

Published
2020
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3. Characterization of Kcnk3 -Mutated Rat, a Novel Model of Pulmonary Hypertension

Author

Thomas Bertero, Catherine Rucker-Martin, David Montani, Laurent Tesson, Marc Humbert, Fabrice Antigny, Frédéric Perros, Séverine Remy, Véronique Capuano, Barbara Girerd, Ignacio Anegon, Boris Manoury, Christine Péchoux, Olaf Mercier, Mélanie Lambert, Valérie Domergue, Morad K. Nakhleh, Aurélie Hautefort, Angèle Boet, Centre chirurgical Marie Lannelongue, Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Biologie et physiopathologie cutanées : expression génique, signalisation et thérapie, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Centre National de la Recherche Scientifique (CNRS), Unité de recherche génomique et physiologie de la lactation (GPL), Institut National de la Recherche Agronomique (INRA), Hypertension arterielle pulmonaire physiopathologie et innovation thérapeutique, Centre chirurgical Marie Lannelongue-Institut National de la Santé et de la Recherche Médicale (INSERM), Détoxication et réparation tissulaire, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Chirurgical Marie Lannelongue (CCML), ANR-18-CE14-0025,MatriPHate,Comprendre la dynamique de la niche vasculaire dans l'hypertension pulmonaire.(2018), Université Paris-Sud 11 - Faculté de médecine (UP11 UFR Médecine), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Côte d'Azur (UCA), Génomique et Physiologie de la Lactation (GPL), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-18-CE14-0025,MATRIPHATE,UNDERSTANDING THE DYNAMIC OF THE VASCULAR NICHE IN PULMONARY HYPERTENSION (PH). MATRIX REPROGRAMMING FORCES PH.(2018), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Centre Chirurgical Marie Lannelongue (CCML)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay, Hôpital Bicêtre, Adhésion et Inflammation (LAI), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Transgenic Rats and Immunophenomics Platform, Partenaires INRAE, Institut de pharmacologie moléculaire et cellulaire (IPMC), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Génétique Animale et Biologie Intégrative (GABI), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Signalisation et physiopathologie cardiovasculaire (CARPAT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Ingénierie et Plateformes au Service de l'Innovation Thérapeutique (IPSIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Université Laval [Québec] (ULaval), Fondation du Souffle et Fonds de Dotation Recherche en Sante Respiratoire from the Fondation Lefoulon-Delalande, Fondation Legs Poix, Therapeutic Innovation Doctoral SchoolED569, ANR-18-CE14-0023,KAPAH,KCNK3 une nouvelle cible thérapeutique dans l'hypertension artérielle pulmonaire(2018), Bertero, Thomas, APPEL À PROJETS GÉNÉRIQUE 2018 - Comprendre la dynamique de la niche vasculaire dans l'hypertension pulmonaire. - - MatriPHate2018 - ANR-18-CE14-0025 - AAPG2018 - VALID, Antigny, Fabrice, and APPEL À PROJETS GÉNÉRIQUE 2018 - KCNK3 une nouvelle cible thérapeutique dans l'hypertension artérielle pulmonaire - - KAPAH2018 - ANR-18-CE14-0023 - AAPG2018 - VALID

Subjects
0301 basic medicine, [SDV.BA] Life Sciences [q-bio]/Animal biology, Physiology, [SDV]Life Sciences [q-bio], [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Rats, Sprague-Dawley, 030204 cardiovascular system & hematology, Extracellular matrix, Exon, 0302 clinical medicine, echocardiography, MESH: Animals, exon, MESH: von Willebrand Factor, MESH: Nerve Tissue Proteins, MESH: Action Potentials, ComputingMilieux_MISCELLANEOUS, Cardiopulmonary disease, education.field_of_study, Potassium channel subfamily K member 3, [SDV.BA]Life Sciences [q-bio]/Animal biology, MESH: Potassium Channels, Tandem Pore Domain, MESH: Blood Pressure, MESH: Muscle, Smooth, Vascular, 3. Good health, [SDV] Life Sciences [q-bio], MESH: Vasoconstriction, medicine.symptom, Cardiology and Cardiovascular Medicine, MESH: Mitogen-Activated Protein Kinase 3, MESH: Nitric Oxide Synthase Type III, MESH: Mitogen-Activated Protein Kinase 1, MESH: Rats, extracellular matrix, MESH: Hypoxia-Inducible Factor 1, alpha Subunit, 03 medical and health sciences, medicine, MESH: Lung, MESH: Survivin, education, Gene, Loss function, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Hypertension, Pulmonary, hypoxia, business.industry, MESH: Loss of Function Mutation, Hypoxia (medical), medicine.disease, Pulmonary hypertension, MESH: Male, rats, 030104 developmental biology, Cancer research, MESH: Disease Models, Animal, business, MESH: Female
Abstract

Rationale: Pulmonary arterial hypertension is a severe lethal cardiopulmonary disease. Loss of function mutations in KCNK3 (potassium channel subfamily K member 3) gene, which encodes an outward rectifier K + channel, have been identified in pulmonary arterial hypertension patients. Objective: We have demonstrated that KCNK3 dysfunction is common to heritable and nonheritable pulmonary arterial hypertension and to experimental pulmonary hypertension (PH). Finally, KCNK3 is not functional in mouse pulmonary vasculature. Methods and Results: Using CRISPR/Cas9 technology, we generated a 94 bp out of frame deletion in exon 1 of Kcnk3 gene and characterized these rats at the electrophysiological, echocardiographic, hemodynamic, morphological, cellular, and molecular levels to decipher the cellular mechanisms associated with loss of KCNK3. Using patch-clamp technique, we validated our transgenic strategy by demonstrating the absence of KCNK3 current in freshly isolated pulmonary arterial smooth muscle cells from Kcnk3 -mutated rats. At 4 months of age, echocardiographic parameters revealed shortening of the pulmonary artery acceleration time associated with elevation of the right ventricular systolic pressure. Kcnk3 -mutated rats developed more severe PH than wild-type rats after monocrotaline exposure or chronic hypoxia exposure. Kcnk3 -mutation induced a lung distal neomuscularization and perivascular extracellular matrix activation. Lungs of Kcnk3 -mutated rats were characterized by overactivation of ERK1/2 (extracellular signal–regulated kinase1-/2), AKT (protein kinase B), SRC, and overexpression of HIF1-α (hypoxia-inducible factor-1 α), survivin, and VWF (Von Willebrand factor). Linked with plasma membrane depolarization, reduced endothelial-NOS expression and desensitization of endothelial-derived hyperpolarizing factor, Kcnk3 -mutated rats presented predisposition to vasoconstriction of pulmonary arteries and a severe loss of sildenafil-induced pulmonary arteries relaxation. Moreover, we showed strong alteration of right ventricular cardiomyocyte excitability. Finally, Kcnk3 -mutated rats developed age-dependent PH associated with low serum-albumin concentration. Conclusions: We established the first Kcnk3 -mutated rat model of PH. Our results confirm that KCNK3 loss of function is a key event in pulmonary arterial hypertension pathogenesis. This model presents new opportunities for understanding the initiating mechanisms of PH and testing biologically relevant therapeutic molecules in the context of PH.

Published
2019
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