Kcnk3 dysfunction exaggerates the development of pulmonary hypertension induced by left ventricular pressure overload.
Animals
Arterial Pressure
Disease Models, Animal
Mutation
Nerve Tissue Proteins
/ genetics
Potassium Channels, Tandem Pore Domain
/ genetics
Pulmonary Arterial Hypertension
/ etiology
Pulmonary Artery
/ metabolism
Rats, Transgenic
Signal Transduction
Vascular Remodeling
Ventricular Dysfunction, Left
/ complications
Ventricular Function, Left
Ventricular Pressure
Ascending-aortic constriction
K2P3.1
PH due to left heart diseases
Proliferation
Task-1
Journal
Cardiovascular research
ISSN: 1755-3245
Titre abrégé: Cardiovasc Res
Pays: England
ID NLM: 0077427
Informations de publication
Date de publication:
01 11 2021
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
2474-2488Subventions
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.