Kcnk3 dysfunction exaggerates the development of pulmonary hypertension induced by left ventricular pressure overload
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissionsoup.com..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:117 |
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| Enthalten in: |
Cardiovascular research - 117(2021), 12 vom: 01. Nov., Seite 2474-2488 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lambert, Mélanie [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 01.02.2022 Date Revised 26.02.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/cvr/cvab016 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM320459063 |
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| 100 | 1 | |a Lambert, Mélanie |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Kcnk3 dysfunction exaggerates the development of pulmonary hypertension induced by left ventricular pressure overload |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Completed 01.02.2022 | ||
| 500 | |a Date Revised 26.02.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissionsoup.com. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Ascending-aortic constriction | |
| 650 | 4 | |a K2P3.1 | |
| 650 | 4 | |a PH due to left heart diseases | |
| 650 | 4 | |a Proliferation | |
| 650 | 4 | |a Task-1 | |
| 650 | 7 | |a Nerve Tissue Proteins |2 NLM | |
| 650 | 7 | |a Potassium Channels, Tandem Pore Domain |2 NLM | |
| 650 | 7 | |a potassium channel subfamily K member 3 |2 NLM | |
| 650 | 7 | |a 1HQ3YCN4GS |2 NLM | |
| 700 | 1 | |a Mendes-Ferreira, Pedro |e verfasserin |4 aut | |
| 700 | 1 | |a Ghigna, Maria-Rosa |e verfasserin |4 aut | |
| 700 | 1 | |a LeRibeuz, Hélène |e verfasserin |4 aut | |
| 700 | 1 | |a Adão, Rui |e verfasserin |4 aut | |
| 700 | 1 | |a Boet, Angèle |e verfasserin |4 aut | |
| 700 | 1 | |a Capuano, Véronique |e verfasserin |4 aut | |
| 700 | 1 | |a Rucker-Martin, Catherine |e verfasserin |4 aut | |
| 700 | 1 | |a Brás-Silva, Carmen |e verfasserin |4 aut | |
| 700 | 1 | |a Quarck, Rozenn |e verfasserin |4 aut | |
| 700 | 1 | |a Domergue, Valérie |e verfasserin |4 aut | |
| 700 | 1 | |a Vachiéry, Jean-Luc |e verfasserin |4 aut | |
| 700 | 1 | |a Humbert, Marc |e verfasserin |4 aut | |
| 700 | 1 | |a Perros, Frédéric |e verfasserin |4 aut | |
| 700 | 1 | |a Montani, David |e verfasserin |4 aut | |
| 700 | 1 | |a Antigny, Fabrice |e verfasserin |4 aut | |
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