SUR1 As a New Therapeutic Target for Pulmonary Arterial Hypertension
Mutations in ABCC8 have been identified in pulmonary arterial hypertension (PAH). ABCC8 encodes SUR1, a regulatory subunit of the ATP-sensitive potassium channel Kir6.2. However, the pathophysiological role of the SUR1/Kir6.2 channel in PAH is unknown. We hypothesized that activation of SUR1 could be a novel potential target for PAH. We analyzed the expression of SUR1/Kir6.2 in the lungs and pulmonary artery (PA) in human PAH or experimental pulmonary hypertension (PH). The contribution of SUR1 in human or rat PA tone was evaluated, and we measured the consequences of in vivo activation of SUR1 in control and PH rats. SUR1 and Kir6.2 protein expression was not reduced in the lungs or human pulmonary arterial endothelial cells and smooth muscle cells from PAH or experimentally induced PH. We showed that pharmacological activation of SUR1 by three different SUR1 activators (diazoxide, VU0071063, and NN414) leads to PA relaxation. Conversely, the inhibition of SUR1/Kir6.2 channels causes PA constriction. In vivo, long- and short-term activation of SUR1 with diazoxide reversed monocrotaline-induced PH in rats. In addition, in vivo diazoxide application (short protocol) reduced the severity of PH in chronic-hypoxia rats. Moreover, 3 weeks of diazoxide exposure in control rats had no cardiovascular effects. Finally, in vivo, activation of SUR1 with NN414 reduced monocrotaline-induced PH in rats. In PAH and experimental PH, the expression of SUR1/Kir6.2 was still present. In vivo pharmacological SUR1 activation by two different molecules alleviated experimental PH, providing proof of concept that SUR1 activation should be considered for PAH and evaluated more thoroughly.
| Errataetall: |
CommentIn: Am J Respir Cell Mol Biol. 2022 May;66(5):476-478. - PMID 35238728 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:66 |
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| Enthalten in: |
American journal of respiratory cell and molecular biology - 66(2022), 5 vom: 17. Mai, Seite 539-554 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Le Ribeuz, Hélène [VerfasserIn] |
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| Links: |
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| Themen: |
73077K8HYV |
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| Anmerkungen: |
Date Completed 03.05.2022 Date Revised 15.06.2022 published: Print CommentIn: Am J Respir Cell Mol Biol. 2022 May;66(5):476-478. - PMID 35238728 Citation Status MEDLINE |
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| doi: |
10.1165/rcmb.2021-0180OC |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM337070814 |
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| 520 | |a Mutations in ABCC8 have been identified in pulmonary arterial hypertension (PAH). ABCC8 encodes SUR1, a regulatory subunit of the ATP-sensitive potassium channel Kir6.2. However, the pathophysiological role of the SUR1/Kir6.2 channel in PAH is unknown. We hypothesized that activation of SUR1 could be a novel potential target for PAH. We analyzed the expression of SUR1/Kir6.2 in the lungs and pulmonary artery (PA) in human PAH or experimental pulmonary hypertension (PH). The contribution of SUR1 in human or rat PA tone was evaluated, and we measured the consequences of in vivo activation of SUR1 in control and PH rats. SUR1 and Kir6.2 protein expression was not reduced in the lungs or human pulmonary arterial endothelial cells and smooth muscle cells from PAH or experimentally induced PH. We showed that pharmacological activation of SUR1 by three different SUR1 activators (diazoxide, VU0071063, and NN414) leads to PA relaxation. Conversely, the inhibition of SUR1/Kir6.2 channels causes PA constriction. In vivo, long- and short-term activation of SUR1 with diazoxide reversed monocrotaline-induced PH in rats. In addition, in vivo diazoxide application (short protocol) reduced the severity of PH in chronic-hypoxia rats. Moreover, 3 weeks of diazoxide exposure in control rats had no cardiovascular effects. Finally, in vivo, activation of SUR1 with NN414 reduced monocrotaline-induced PH in rats. In PAH and experimental PH, the expression of SUR1/Kir6.2 was still present. In vivo pharmacological SUR1 activation by two different molecules alleviated experimental PH, providing proof of concept that SUR1 activation should be considered for PAH and evaluated more thoroughly | ||
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| 700 | 1 | |a Capuano, Véronique |e verfasserin |4 aut | |
| 700 | 1 | |a Dutheil, Mary |e verfasserin |4 aut | |
| 700 | 1 | |a Gooroochurn, Hans |e verfasserin |4 aut | |
| 700 | 1 | |a Boët, Angèle |e verfasserin |4 aut | |
| 700 | 1 | |a Ghigna, Maria-Rosa |e verfasserin |4 aut | |
| 700 | 1 | |a De Montpreville, Vincent |e verfasserin |4 aut | |
| 700 | 1 | |a Girerd, Barbara |e verfasserin |4 aut | |
| 700 | 1 | |a Lambert, Mélanie |e verfasserin |4 aut | |
| 700 | 1 | |a Mercier, Olaf |e verfasserin |4 aut | |
| 700 | 1 | |a Chung, Wendy K |e verfasserin |4 aut | |
| 700 | 1 | |a Humbert, Marc |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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