SUR1/Kir6.2 potassium channel a new actor involved in pulmonary arterial hypertension - 25/09/20
Résumé |
Background |
Recently mutations in ABBC8 have been identified in patients with pulmonary arterial hypertension (PAH). ABCC8 encodes SUR1 a regulatory subunit of the ATP-sensitive potassium channel Kir6.2. In 2018, Bohnen M et al., demonstrated that each identified ABCC8 mutation leads to a loss of ABCC8/Kir6.2 function. However, the role of SUR1/Kir6.2 channel in PAH is unclear. We hypothesized that SUR1/Kir6.2 dysfunction contributes to pulmonary arteries (PA) remodeling in PAH and consequently, pharmacological activation of Sur1/Kir6.2 function could alleviate experimental pulmonary hypertension (PH)
Methods and results |
We demonstrated that SUR1 and Kir6.2 expression are not significantly altered in lung and PA from human PAH or experimental models of PAH (monocrotaline (MCT) and Sugen/Hypoxia rats). In contrast, SUR1 and Kir6.2 expression are strongly reduced in right ventricular tissues from MCT rats. Using myograph experiments on isolated PA we showed that pharmacological activation of SUR1/Kir6.2 channels by diazoxide leads to PA relaxation. Moreover, the pharmacological inhibition of SUR1/Kir6.2 channels by nateglinide (100μmol/L) before treatment with a thromboxane A2 mimetic causes PA hypercontraction. In vivo, long term (during 3 weeks of MCT-exposure) pharmacological activation of SUR1/Kir6.2 with diazoxide (20mg/kg/day) significantly prevented MCT-induced PH in rats. Additionally, in vivo short term administration of diazoxide (last week of MCT-exposure) improved cardiac output and pulmonary vascular resistance. Finally, long-term exposure (3 weeks) to diazoxide in control rats had no consequences on hemodynamics, demonstrating the safety of this compound.
Conclusions |
In PAH and experimental PH, SUR1/Kir6.2 expression are the same as in controls. In vivo long term pharmacological activation of SUR1/Kir6.2 alleviated MCT-induced PH. These results demonstrate that SUR1/Kir6.2 should be considered as a new therapeutic target and evaluated more thoroughly.
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Vol 12 - N° 2-4
P. 214 - octobre 2020 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.