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


Journal

Cardiovascular research
ISSN: 1755-3245
Titre abrégé: Cardiovasc Res
Pays: England
ID NLM: 0077427

Informations de publication

Date de publication:
01 11 2021
Historique:
received: 17 06 2020
accepted: 09 01 2021
pubmed: 24 1 2021
medline: 2 2 2022
entrez: 23 1 2021
Statut: ppublish

Résumé

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. 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. 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.

Identifiants

pubmed: 33483721
pii: 6105230
doi: 10.1093/cvr/cvab016
doi:

Substances chimiques

Nerve Tissue Proteins 0
Potassium Channels, Tandem Pore Domain 0
potassium channel subfamily K member 3 1HQ3YCN4GS

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2474-2488

Subventions

Organisme : French National Institute for Health and Medical Research (INSERM)
Organisme : Université Paris-Saclay
Organisme : Marie Lannelongue Hospital
Organisme : French National Agency for Research (ANR)
ID : ANR-18-CE14-0023
Organisme : Fondation maladies rares in the frame of the 'Small animal models and rare diseases' programme to generate the Kcnk3-mutaed
Organisme : Therapeutic Innovation Doctoral School
ID : ED569
Organisme : Portuguese Foundation for Science and Technology
ID : UID/IC/00051/2013
Organisme : IMPAcT
ID : PTDC/MED-FSL/31719/2017
Organisme : NETDIAMOND
ID : POCI-01-0145-FEDER-016385

Informations de copyright

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Auteurs

Mélanie Lambert (M)

Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre,France.
Assistance Publique Hôpitaux de Paris, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire, Hôpital Bicêtre, Le Kremlin Bicêtre, France.
Inserm UMR_S 999, Hôpital Marie Lannelongue, 133, Avenue de la Résistance, F-92350 Le Plessis Robinson,France.

Pedro Mendes-Ferreira (P)

Cardiovascular R&D Center, Faculty of Medicine of the University of Porto, Porto,Portugal.
Laboratory of Respiratory Diseases & Thoracic Surgery (BREATHE), Department of Chronic Diseases & Metabolism (CHROMETA), KU Leuven-University of Leuven, Leuven,Belgium.

Maria-Rosa Ghigna (MR)

Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre,France.
Assistance Publique Hôpitaux de Paris, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire, Hôpital Bicêtre, Le Kremlin Bicêtre, France.
Inserm UMR_S 999, Hôpital Marie Lannelongue, 133, Avenue de la Résistance, F-92350 Le Plessis Robinson,France.

Hélène LeRibeuz (H)

Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre,France.
Assistance Publique Hôpitaux de Paris, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire, Hôpital Bicêtre, Le Kremlin Bicêtre, France.
Inserm UMR_S 999, Hôpital Marie Lannelongue, 133, Avenue de la Résistance, F-92350 Le Plessis Robinson,France.

Rui Adão (R)

Cardiovascular R&D Center, Faculty of Medicine of the University of Porto, Porto,Portugal.

Angèle Boet (A)

Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre,France.
Assistance Publique Hôpitaux de Paris, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire, Hôpital Bicêtre, Le Kremlin Bicêtre, France.
Inserm UMR_S 999, Hôpital Marie Lannelongue, 133, Avenue de la Résistance, F-92350 Le Plessis Robinson,France.

Véronique Capuano (V)

Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre,France.
Assistance Publique Hôpitaux de Paris, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire, Hôpital Bicêtre, Le Kremlin Bicêtre, France.
Inserm UMR_S 999, Hôpital Marie Lannelongue, 133, Avenue de la Résistance, F-92350 Le Plessis Robinson,France.

Catherine Rucker-Martin (C)

Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre,France.
Assistance Publique Hôpitaux de Paris, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire, Hôpital Bicêtre, Le Kremlin Bicêtre, France.
Inserm UMR_S 999, Hôpital Marie Lannelongue, 133, Avenue de la Résistance, F-92350 Le Plessis Robinson,France.

Carmen Brás-Silva (C)

Cardiovascular R&D Center, Faculty of Medicine of the University of Porto, Porto,Portugal.

Rozenn Quarck (R)

Laboratory of Respiratory Diseases & Thoracic Surgery (BREATHE), Department of Chronic Diseases & Metabolism (CHROMETA), KU Leuven-University of Leuven, Leuven,Belgium.
Clinical Department of Respiratory Diseases, University Hospitals of Leuven, Leuven, Belgium.

Valérie Domergue (V)

Animal Facility, Institut Paris Saclay d'Innovation Thérapeutique (UMS IPSIT), Université Paris-Saclay, Châtenay-Malabry, France.

Jean-Luc Vachiéry (JL)

Department of Cardiology, Cliniques Universitaires de Bruxelles-Hôpital Erasme, Brussels, Belgium.

Marc Humbert (M)

Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre,France.
Assistance Publique Hôpitaux de Paris, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire, Hôpital Bicêtre, Le Kremlin Bicêtre, France.
Inserm UMR_S 999, Hôpital Marie Lannelongue, 133, Avenue de la Résistance, F-92350 Le Plessis Robinson,France.

Frédéric Perros (F)

Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre,France.
Assistance Publique Hôpitaux de Paris, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire, Hôpital Bicêtre, Le Kremlin Bicêtre, France.
Inserm UMR_S 999, Hôpital Marie Lannelongue, 133, Avenue de la Résistance, F-92350 Le Plessis Robinson,France.

David Montani (D)

Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre,France.
Assistance Publique Hôpitaux de Paris, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire, Hôpital Bicêtre, Le Kremlin Bicêtre, France.
Inserm UMR_S 999, Hôpital Marie Lannelongue, 133, Avenue de la Résistance, F-92350 Le Plessis Robinson,France.

Fabrice Antigny (F)

Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre,France.
Assistance Publique Hôpitaux de Paris, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire, Hôpital Bicêtre, Le Kremlin Bicêtre, France.
Inserm UMR_S 999, Hôpital Marie Lannelongue, 133, Avenue de la Résistance, F-92350 Le Plessis Robinson,France.

Articles similaires

Robotic Surgical Procedures Animals Humans Telemedicine Models, Animal

Odour generalisation and detection dog training.

Lyn Caldicott, Thomas W Pike, Helen E Zulch et al.
1.00
Animals Odorants Dogs Generalization, Psychological Smell
Animals TOR Serine-Threonine Kinases Colorectal Neoplasms Colitis Mice
Animals Tail Swine Behavior, Animal Animal Husbandry

Classifications MeSH