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Implication of the KATP Sur2b/Kir6.1 in the physiopathology of pulmonary arterial hypertension - 09/03/22

Doi : 10.1016/j.rmr.2022.02.027 
H. Le Ribeuz 1, 2, , M. Dutheil 1, 2, V. Capuano 1, 2, O. Mercier 3, M. Humbert 1, 2, 4, D. Montani 1, 2, 4, F. Antigny 1, 2
1 Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France 
2 INSERM UMR_S 999 «Hypertension pulmonaire: Physiopathologie et Innovation Thérapeutique», Hôpital Marie Lannelongue, Le Plessis-Robinson, France 
3 Service de Chirurgie Thoracique, Vasculaire et Transplantation Cardio-Pulmonaire, Hôpital Marie Lannelongue, Groupe Hospitalier Paris Saint Joseph, Le Plessis Robinson, France 
4 Assistance 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, France 

Corresponding author.

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Résumé

Background

PAH is a severe cardiopulmonary disease which is defined by an elevation of the mPAP >25mmHg. ABCC9 mutations are responsible of Cantu syndrome, a disease characterised by several cardiac disorders and for some case pulmonary hypertension. ABCC9 gene encodes for SUR2 protein, a regulatory subunit of KATP channels. We hypothesized that SUR2/Kir6.1 channel contributes to PAH pathogenesis and could be a therapeutic target in PAH.

Methods

We used a combination of in vitro, ex-vivo and in vitro approaches to analyse localisation, expression and function (proliferation, migration and contraction) of SUR2/Kir6.1 in PAH physiopathology. Finally, we performed in vivo pharmacological activation of SUR2/Kir6.1 with pinacidil on MCT induced-PH rats.

Results

We demonstrated that SUR2A, SUR2B and Kir6.1 are expressed in lungs from control and PAH patients and in experimental-PH models. Myograph experiments demonstrated that pharmacological activation of SUR2 induced pulmonary arterial relaxation in human and rat isolated pulmonary arteries. PA relaxation was still present in PA from MCT-rats but reduced compared to control rats. In vitro experiments on human PASMCs from control and PAH patients show a decrease of the cell proliferation and migration after SUR2 activation. Finally, pharmacological activation in vivo of SUR2 on MCT induced-PH rats show an improvement of the hemodynamic parameters in preventive and curative protocol.

Conclusion

This study demonstrates the role of SUR2B/Kir6.1on pulmonary vasculature and provides the proof of concept that it's pharmacological activation could be a therapeutic option for PAH.

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Keyword : Circulation


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© 2022  Publié par Elsevier Masson SAS.
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Vol 39 - N° 2

P. 119 - février 2022 Retour au numéro
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