{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T17:19:36Z","timestamp":1775841576049,"version":"3.50.1"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2021,1,23]],"date-time":"2021-01-23T00:00:00Z","timestamp":1611360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"French National Institute for Health and Medical Research"},{"DOI":"10.13039\/501100007241","name":"Universit\u00e9 Paris-Saclay","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007241","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Marie Lannelongue Hospital"},{"name":"French National Agency for Research","award":["ANR-18-CE14-0023"],"award-info":[{"award-number":["ANR-18-CE14-0023"]}]},{"name":"Fondation maladies rares in the frame of the \u2018Small animal models and rare diseases\u2019 programme to generate the Kcnk3-mutaed"},{"name":"Therapeutic Innovation Doctoral School","award":["ED569"],"award-info":[{"award-number":["ED569"]}]},{"name":"Portuguese Foundation for Science and Technology","award":["UID\/IC\/00051\/2013"],"award-info":[{"award-number":["UID\/IC\/00051\/2013"]}]},{"name":"Portuguese Foundation for Science and Technology","award":["COMPETE_2020, POCI"],"award-info":[{"award-number":["COMPETE_2020, POCI"]}]},{"name":"IMPAcT","award":["PTDC\/MED-FSL\/31719\/2017"],"award-info":[{"award-number":["PTDC\/MED-FSL\/31719\/2017"]}]},{"name":"IMPAcT","award":["POCI-01-0145-FEDER-031719"],"award-info":[{"award-number":["POCI-01-0145-FEDER-031719"]}]},{"name":"NETDIAMOND","award":["POCI-01-0145-FEDER-016385"],"award-info":[{"award-number":["POCI-01-0145-FEDER-016385"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvab016","type":"journal-article","created":{"date-parts":[[2021,1,10]],"date-time":"2021-01-10T06:46:00Z","timestamp":1610261160000},"page":"2474-2488","source":"Crossref","is-referenced-by-count":32,"title":["Kcnk3 dysfunction exaggerates the development of pulmonary hypertension induced by left ventricular pressure overload"],"prefix":"10.1093","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2742-2575","authenticated-orcid":false,"given":"M\u00e9lanie","family":"Lambert","sequence":"first","affiliation":[{"name":"Univ. Paris\u2013Sud, Facult\u00e9 de M\u00e9decine, Universit\u00e9 Paris-Saclay, Le Kremlin Bic\u00eatre,France"},{"name":"Assistance Publique H\u00f4pitaux de Paris, Service de Pneumologie, Centre de R\u00e9f\u00e9rence de l\u2019Hypertension Pulmonaire, H\u00f4pital Bic\u00eatre, Le Kremlin Bic\u00eatre, France"},{"name":"Inserm UMR_S 999, H\u00f4pital Marie Lannelongue, 133, Avenue de la R\u00e9sistance, F-92350 Le Plessis Robinson,France"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3616-6785","authenticated-orcid":false,"given":"Pedro","family":"Mendes-Ferreira","sequence":"additional","affiliation":[{"name":"Cardiovascular R&D Center, Faculty of Medicine of the University of Porto, Porto,Portugal"},{"name":"Laboratory of Respiratory Diseases & Thoracic Surgery (BREATHE), Department of Chronic Diseases & Metabolism (CHROMETA), KU Leuven\u2014University of Leuven, Leuven,Belgium"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5996-665X","authenticated-orcid":false,"given":"Maria-Rosa","family":"Ghigna","sequence":"additional","affiliation":[{"name":"Univ. Paris\u2013Sud, Facult\u00e9 de M\u00e9decine, Universit\u00e9 Paris-Saclay, Le Kremlin Bic\u00eatre,France"},{"name":"Assistance Publique H\u00f4pitaux de Paris, Service de Pneumologie, Centre de R\u00e9f\u00e9rence de l\u2019Hypertension Pulmonaire, H\u00f4pital Bic\u00eatre, Le Kremlin Bic\u00eatre, France"},{"name":"Inserm UMR_S 999, H\u00f4pital Marie Lannelongue, 133, Avenue de la R\u00e9sistance, F-92350 Le Plessis Robinson,France"}]},{"given":"H\u00e9l\u00e8ne","family":"LeRibeuz","sequence":"additional","affiliation":[{"name":"Univ. Paris\u2013Sud, Facult\u00e9 de M\u00e9decine, Universit\u00e9 Paris-Saclay, Le Kremlin Bic\u00eatre,France"},{"name":"Assistance Publique H\u00f4pitaux de Paris, Service de Pneumologie, Centre de R\u00e9f\u00e9rence de l\u2019Hypertension Pulmonaire, H\u00f4pital Bic\u00eatre, Le Kremlin Bic\u00eatre, France"},{"name":"Inserm UMR_S 999, H\u00f4pital Marie Lannelongue, 133, Avenue de la R\u00e9sistance, F-92350 Le Plessis Robinson,France"}]},{"given":"Rui","family":"Ad\u00e3o","sequence":"additional","affiliation":[{"name":"Cardiovascular R&D Center, Faculty of Medicine of the University of Porto, Porto,Portugal"}]},{"given":"Ang\u00e8le","family":"Boet","sequence":"additional","affiliation":[{"name":"Univ. Paris\u2013Sud, Facult\u00e9 de M\u00e9decine, Universit\u00e9 Paris-Saclay, Le Kremlin Bic\u00eatre,France"},{"name":"Assistance Publique H\u00f4pitaux de Paris, Service de Pneumologie, Centre de R\u00e9f\u00e9rence de l\u2019Hypertension Pulmonaire, H\u00f4pital Bic\u00eatre, Le Kremlin Bic\u00eatre, France"},{"name":"Inserm UMR_S 999, H\u00f4pital Marie Lannelongue, 133, Avenue de la R\u00e9sistance, F-92350 Le Plessis Robinson,France"}]},{"given":"V\u00e9ronique","family":"Capuano","sequence":"additional","affiliation":[{"name":"Univ. Paris\u2013Sud, Facult\u00e9 de M\u00e9decine, Universit\u00e9 Paris-Saclay, Le Kremlin Bic\u00eatre,France"},{"name":"Assistance Publique H\u00f4pitaux de Paris, Service de Pneumologie, Centre de R\u00e9f\u00e9rence de l\u2019Hypertension Pulmonaire, H\u00f4pital Bic\u00eatre, Le Kremlin Bic\u00eatre, France"},{"name":"Inserm UMR_S 999, H\u00f4pital Marie Lannelongue, 133, Avenue de la R\u00e9sistance, F-92350 Le Plessis Robinson,France"}]},{"given":"Catherine","family":"Rucker-Martin","sequence":"additional","affiliation":[{"name":"Univ. Paris\u2013Sud, Facult\u00e9 de M\u00e9decine, Universit\u00e9 Paris-Saclay, Le Kremlin Bic\u00eatre,France"},{"name":"Assistance Publique H\u00f4pitaux de Paris, Service de Pneumologie, Centre de R\u00e9f\u00e9rence de l\u2019Hypertension Pulmonaire, H\u00f4pital Bic\u00eatre, Le Kremlin Bic\u00eatre, France"},{"name":"Inserm UMR_S 999, H\u00f4pital Marie Lannelongue, 133, Avenue de la R\u00e9sistance, F-92350 Le Plessis Robinson,France"}]},{"given":"Carmen","family":"Br\u00e1s-Silva","sequence":"additional","affiliation":[{"name":"Cardiovascular R&D Center, Faculty of Medicine of the University of Porto, Porto,Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8293-6261","authenticated-orcid":false,"given":"Rozenn","family":"Quarck","sequence":"additional","affiliation":[{"name":"Laboratory of Respiratory Diseases & Thoracic Surgery (BREATHE), Department of Chronic Diseases & Metabolism (CHROMETA), KU Leuven\u2014University of Leuven, Leuven,Belgium"},{"name":"Clinical Department of Respiratory Diseases, University Hospitals of Leuven, Leuven, Belgium"}]},{"given":"Val\u00e9rie","family":"Domergue","sequence":"additional","affiliation":[{"name":"Animal Facility, Institut Paris Saclay d\u2019Innovation Th\u00e9rapeutique (UMS IPSIT), Universit\u00e9 Paris-Saclay, Ch\u00e2tenay-Malabry, France"}]},{"given":"Jean-Luc","family":"Vachi\u00e9ry","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Cliniques Universitaires de Bruxelles\u2014H\u00f4pital Erasme, Brussels, Belgium"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0703-2892","authenticated-orcid":false,"given":"Marc","family":"Humbert","sequence":"additional","affiliation":[{"name":"Univ. Paris\u2013Sud, Facult\u00e9 de M\u00e9decine, Universit\u00e9 Paris-Saclay, Le Kremlin Bic\u00eatre,France"},{"name":"Assistance Publique H\u00f4pitaux de Paris, Service de Pneumologie, Centre de R\u00e9f\u00e9rence de l\u2019Hypertension Pulmonaire, H\u00f4pital Bic\u00eatre, Le Kremlin Bic\u00eatre, France"},{"name":"Inserm UMR_S 999, H\u00f4pital Marie Lannelongue, 133, Avenue de la R\u00e9sistance, F-92350 Le Plessis Robinson,France"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7730-2427","authenticated-orcid":false,"given":"Fr\u00e9d\u00e9ric","family":"Perros","sequence":"additional","affiliation":[{"name":"Univ. 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