Involvement of SUR2/Kir6.1 channel in the physiopathology of pulmonary arterial hypertension
AimsWe hypothesized that the ATP-sensitive K+ channels (KATP) regulatory subunit (ABCC9) contributes to PAH pathogenesis. ABCC9 gene encodes for two regulatory subunits of KATP channels: the SUR2A and SUR2B proteins. In the KATP channel, the SUR2 subunits are associated with the K+ channel Kir6.1. W...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-01-01
|
| Series: | Frontiers in Cardiovascular Medicine |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2022.1066047/full |
| _version_ | 1797956445564567552 |
|---|---|
| author | Hélène Le Ribeuz Hélène Le Ribeuz Bastien Masson Bastien Masson Mary Dutheil Mary Dutheil Mary Dutheil Angèle Boët Angèle Boët Antoine Beauvais Antoine Beauvais Jessica Sabourin Vincent Thomas De Montpreville Véronique Capuano Véronique Capuano Véronique Capuano Olaf Mercier Marc Humbert Marc Humbert Marc Humbert David Montani David Montani David Montani Fabrice Antigny Fabrice Antigny |
| author_facet | Hélène Le Ribeuz Hélène Le Ribeuz Bastien Masson Bastien Masson Mary Dutheil Mary Dutheil Mary Dutheil Angèle Boët Angèle Boët Antoine Beauvais Antoine Beauvais Jessica Sabourin Vincent Thomas De Montpreville Véronique Capuano Véronique Capuano Véronique Capuano Olaf Mercier Marc Humbert Marc Humbert Marc Humbert David Montani David Montani David Montani Fabrice Antigny Fabrice Antigny |
| author_sort | Hélène Le Ribeuz |
| collection | DOAJ |
| description | AimsWe hypothesized that the ATP-sensitive K+ channels (KATP) regulatory subunit (ABCC9) contributes to PAH pathogenesis. ABCC9 gene encodes for two regulatory subunits of KATP channels: the SUR2A and SUR2B proteins. In the KATP channel, the SUR2 subunits are associated with the K+ channel Kir6.1. We investigated how the SUR2/Kir6.1 channel contributes to PAH pathogenesis and its potential as a therapeutic target in PAH.Methods and resultsUsing in vitro, ex vivo, and in vivo approaches, we analyzed the localization and expression of SUR2A, SUR2B, and Kir6.1 in the pulmonary vasculature of controls and patients with PAH as in experimental pulmonary hypertension (PH) rat models and its contribution to PAH physiopathology. Finally, we deciphered the consequences of in vivo activation of SUR2/Kir6.1 in the monocrotaline (MCT)-induced PH model. We found that SUR2A, SUR2B, and Kir6.1 were expressed in the lungs of controls and patients with PAH and MCT-induced PH rat models. Organ bath studies showed that SUR2 activation by pinacidil induced relaxation of pulmonary arterial in rats and humans. In vitro experiments on human pulmonary arterial smooth muscle cells and endothelial cells (hPASMCs and hPAECs) in controls and PAH patients showed decreased cell proliferation and migration after SUR2 activation. We demonstrated that SUR2 activation in rat right ventricular (RV) cardiomyocytes reduced RV action potential duration by patch-clamp. Chronic pinacidil administration in control rats increased heart rate without changes in hemodynamic parameters. Finally, in vivo pharmacological activation of SUR2 on MCT and Chronic-hypoxia (CH)-induced-PH rats showed improved PH.ConclusionWe showed that SUR2A, SUR2B, and Kir6.1 are presented in hPASMCs and hPAECs of controls and PAH patients. In vivo SUR2 activation reduced the MCT-induced and CH-induced PH phenotype, suggesting that SUR2 activation should be considered for treating PAH. |
| first_indexed | 2024-04-10T23:50:25Z |
| format | Article |
| id | doaj.art-99c8714ef1d44eb39bf6aad8c7b0d47e |
| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-04-10T23:50:25Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-99c8714ef1d44eb39bf6aad8c7b0d47e2023-01-10T20:06:47ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2023-01-01910.3389/fcvm.2022.10660471066047Involvement of SUR2/Kir6.1 channel in the physiopathology of pulmonary arterial hypertensionHélène Le Ribeuz0Hélène Le Ribeuz1Bastien Masson2Bastien Masson3Mary Dutheil4Mary Dutheil5Mary Dutheil6Angèle Boët7Angèle Boët8Antoine Beauvais9Antoine Beauvais10Jessica Sabourin11Vincent Thomas De Montpreville12Véronique Capuano13Véronique Capuano14Véronique Capuano15Olaf Mercier16Marc Humbert17Marc Humbert18Marc Humbert19David Montani20David Montani21David Montani22Fabrice Antigny23Fabrice Antigny24Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, FranceINSERM UMR_S 999 « Hypertension Pulmonaire Physiopathologie et Innovation Thérapeutique », Hôpital Marie Lannelongue, Le Plessis-Robinson, FranceUniversité Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, FranceINSERM UMR_S 999 « Hypertension Pulmonaire Physiopathologie et Innovation Thérapeutique », Hôpital Marie Lannelongue, Le Plessis-Robinson, FranceUniversité Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, FranceINSERM UMR_S 999 « Hypertension Pulmonaire Physiopathologie et Innovation Thérapeutique », Hôpital Marie Lannelongue, Le Plessis-Robinson, FranceHôptal Marie Lannelongue, Groupe Hospitalier Paris Saint-Joseph, Le Plessis Robinson, FranceUniversité Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, FranceINSERM UMR_S 999 « Hypertension Pulmonaire Physiopathologie et Innovation Thérapeutique », Hôpital Marie Lannelongue, Le Plessis-Robinson, FranceUniversité Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, FranceINSERM UMR_S 999 « Hypertension Pulmonaire Physiopathologie et Innovation Thérapeutique », Hôpital Marie Lannelongue, Le Plessis-Robinson, FranceInserm, UMR-S 1180, Signalisation et Physiopathologie Cardiovasculaire, Université Paris-Saclay, Orsay, FranceDepartment of Pathology, Hôptal Marie Lannelongue, Groupe Hospitalier Paris Saint-Joseph, Le Plessis-Robinson, FranceUniversité Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, FranceINSERM UMR_S 999 « Hypertension Pulmonaire Physiopathologie et Innovation Thérapeutique », Hôpital Marie Lannelongue, Le Plessis-Robinson, FranceHôptal Marie Lannelongue, Groupe Hospitalier Paris Saint-Joseph, Le Plessis Robinson, FranceService de Chirurgie Thoracique, Vasculaire et Transplantation Cardio-Pulmonaire, Hôpital Marie Lannelongue, Groupe Hospitalier Paris Saint Joseph, Le Plessis Robinson, FranceUniversité Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, FranceINSERM UMR_S 999 « Hypertension Pulmonaire Physiopathologie et Innovation Thérapeutique », Hôpital Marie Lannelongue, Le Plessis-Robinson, FranceAssistance Publique–Hôpitaux de Paris (AP-HP), Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de l’Hypertension Pulmonaire, Hôpital Bicêtre, Le Kremlin-Bicêtre, FranceUniversité Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, FranceINSERM UMR_S 999 « Hypertension Pulmonaire Physiopathologie et Innovation Thérapeutique », Hôpital Marie Lannelongue, Le Plessis-Robinson, FranceAssistance Publique–Hôpitaux de Paris (AP-HP), Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de l’Hypertension Pulmonaire, Hôpital Bicêtre, Le Kremlin-Bicêtre, FranceUniversité Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, FranceINSERM UMR_S 999 « Hypertension Pulmonaire Physiopathologie et Innovation Thérapeutique », Hôpital Marie Lannelongue, Le Plessis-Robinson, FranceAimsWe hypothesized that the ATP-sensitive K+ channels (KATP) regulatory subunit (ABCC9) contributes to PAH pathogenesis. ABCC9 gene encodes for two regulatory subunits of KATP channels: the SUR2A and SUR2B proteins. In the KATP channel, the SUR2 subunits are associated with the K+ channel Kir6.1. We investigated how the SUR2/Kir6.1 channel contributes to PAH pathogenesis and its potential as a therapeutic target in PAH.Methods and resultsUsing in vitro, ex vivo, and in vivo approaches, we analyzed the localization and expression of SUR2A, SUR2B, and Kir6.1 in the pulmonary vasculature of controls and patients with PAH as in experimental pulmonary hypertension (PH) rat models and its contribution to PAH physiopathology. Finally, we deciphered the consequences of in vivo activation of SUR2/Kir6.1 in the monocrotaline (MCT)-induced PH model. We found that SUR2A, SUR2B, and Kir6.1 were expressed in the lungs of controls and patients with PAH and MCT-induced PH rat models. Organ bath studies showed that SUR2 activation by pinacidil induced relaxation of pulmonary arterial in rats and humans. In vitro experiments on human pulmonary arterial smooth muscle cells and endothelial cells (hPASMCs and hPAECs) in controls and PAH patients showed decreased cell proliferation and migration after SUR2 activation. We demonstrated that SUR2 activation in rat right ventricular (RV) cardiomyocytes reduced RV action potential duration by patch-clamp. Chronic pinacidil administration in control rats increased heart rate without changes in hemodynamic parameters. Finally, in vivo pharmacological activation of SUR2 on MCT and Chronic-hypoxia (CH)-induced-PH rats showed improved PH.ConclusionWe showed that SUR2A, SUR2B, and Kir6.1 are presented in hPASMCs and hPAECs of controls and PAH patients. In vivo SUR2 activation reduced the MCT-induced and CH-induced PH phenotype, suggesting that SUR2 activation should be considered for treating PAH.https://www.frontiersin.org/articles/10.3389/fcvm.2022.1066047/fullATPABCC9pulmonary arterial tonemigrationproliferationmetabolism |
| spellingShingle | Hélène Le Ribeuz Hélène Le Ribeuz Bastien Masson Bastien Masson Mary Dutheil Mary Dutheil Mary Dutheil Angèle Boët Angèle Boët Antoine Beauvais Antoine Beauvais Jessica Sabourin Vincent Thomas De Montpreville Véronique Capuano Véronique Capuano Véronique Capuano Olaf Mercier Marc Humbert Marc Humbert Marc Humbert David Montani David Montani David Montani Fabrice Antigny Fabrice Antigny Involvement of SUR2/Kir6.1 channel in the physiopathology of pulmonary arterial hypertension Frontiers in Cardiovascular Medicine ATP ABCC9 pulmonary arterial tone migration proliferation metabolism |
| title | Involvement of SUR2/Kir6.1 channel in the physiopathology of pulmonary arterial hypertension |
| title_full | Involvement of SUR2/Kir6.1 channel in the physiopathology of pulmonary arterial hypertension |
| title_fullStr | Involvement of SUR2/Kir6.1 channel in the physiopathology of pulmonary arterial hypertension |
| title_full_unstemmed | Involvement of SUR2/Kir6.1 channel in the physiopathology of pulmonary arterial hypertension |
| title_short | Involvement of SUR2/Kir6.1 channel in the physiopathology of pulmonary arterial hypertension |
| title_sort | involvement of sur2 kir6 1 channel in the physiopathology of pulmonary arterial hypertension |
| topic | ATP ABCC9 pulmonary arterial tone migration proliferation metabolism |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2022.1066047/full |
| work_keys_str_mv | AT heleneleribeuz involvementofsur2kir61channelinthephysiopathologyofpulmonaryarterialhypertension AT heleneleribeuz involvementofsur2kir61channelinthephysiopathologyofpulmonaryarterialhypertension AT bastienmasson involvementofsur2kir61channelinthephysiopathologyofpulmonaryarterialhypertension AT bastienmasson involvementofsur2kir61channelinthephysiopathologyofpulmonaryarterialhypertension AT marydutheil involvementofsur2kir61channelinthephysiopathologyofpulmonaryarterialhypertension AT marydutheil involvementofsur2kir61channelinthephysiopathologyofpulmonaryarterialhypertension AT marydutheil involvementofsur2kir61channelinthephysiopathologyofpulmonaryarterialhypertension AT angeleboet involvementofsur2kir61channelinthephysiopathologyofpulmonaryarterialhypertension AT angeleboet involvementofsur2kir61channelinthephysiopathologyofpulmonaryarterialhypertension AT antoinebeauvais involvementofsur2kir61channelinthephysiopathologyofpulmonaryarterialhypertension AT antoinebeauvais involvementofsur2kir61channelinthephysiopathologyofpulmonaryarterialhypertension AT jessicasabourin involvementofsur2kir61channelinthephysiopathologyofpulmonaryarterialhypertension AT vincentthomasdemontpreville involvementofsur2kir61channelinthephysiopathologyofpulmonaryarterialhypertension AT veroniquecapuano involvementofsur2kir61channelinthephysiopathologyofpulmonaryarterialhypertension AT veroniquecapuano involvementofsur2kir61channelinthephysiopathologyofpulmonaryarterialhypertension AT veroniquecapuano involvementofsur2kir61channelinthephysiopathologyofpulmonaryarterialhypertension AT olafmercier involvementofsur2kir61channelinthephysiopathologyofpulmonaryarterialhypertension AT marchumbert involvementofsur2kir61channelinthephysiopathologyofpulmonaryarterialhypertension AT marchumbert involvementofsur2kir61channelinthephysiopathologyofpulmonaryarterialhypertension AT marchumbert involvementofsur2kir61channelinthephysiopathologyofpulmonaryarterialhypertension AT davidmontani involvementofsur2kir61channelinthephysiopathologyofpulmonaryarterialhypertension AT davidmontani involvementofsur2kir61channelinthephysiopathologyofpulmonaryarterialhypertension AT davidmontani involvementofsur2kir61channelinthephysiopathologyofpulmonaryarterialhypertension AT fabriceantigny involvementofsur2kir61channelinthephysiopathologyofpulmonaryarterialhypertension AT fabriceantigny involvementofsur2kir61channelinthephysiopathologyofpulmonaryarterialhypertension |