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

Author:

Lambert Mélanie123ORCID,Mendes-Ferreira Pedro45ORCID,Ghigna Maria-Rosa123ORCID,LeRibeuz Hélène123,Adão Rui4,Boet Angèle123,Capuano Véronique123,Rucker-Martin Catherine123,Brás-Silva Carmen4,Quarck Rozenn56ORCID,Domergue Valérie7,Vachiéry Jean-Luc8,Humbert Marc123ORCID,Perros Frédéric123ORCID,Montani David123ORCID,Antigny Fabrice123ORCID

Affiliation:

1. Univ. Paris–Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre,France

2. Assistance Publique Hôpitaux de Paris, Service de Pneumologie, Centre de Référence de l’Hypertension Pulmonaire, Hôpital Bicêtre, Le Kremlin Bicêtre, France

3. Inserm UMR_S 999, Hôpital Marie Lannelongue, 133, Avenue de la Résistance, F-92350 Le Plessis Robinson,France

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

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

6. Clinical Department of Respiratory Diseases, University Hospitals of Leuven, Leuven, Belgium

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

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

Abstract

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.

Funder

French National Institute for Health and Medical Research

Université Paris-Saclay

Marie Lannelongue Hospital

French National Agency for Research

Fondation maladies rares in the frame of the ‘Small animal models and rare diseases’ programme to generate the Kcnk3-mutaed

Therapeutic Innovation Doctoral School

Portuguese Foundation for Science and Technology

IMPAcT

NETDIAMOND

Publisher

Oxford University Press (OUP)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

Reference50 articles.

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4. Fasudil preserves lung endothelial function and reduces pulmonary vascular remodeling in a rat model of end-stage pulmonary hypertension with left heart disease;Zhuang;Int J Mol Med,2018

5. Inhaled nitric oxide versus aerosolized iloprost for the treatment of pulmonary hypertension with left heart disease;Yin;Crit Care Med,2009

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