LAUSR

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 mutat.ion leads to a loss of ABCC8/Kir6.2 function. However, the role of this channel in PAH is unclear. Aim and Objectives: We hypothesized that SUR1/Kir6.2 dysfunction contributes to pulmonary arteries remodeling in PAH and consequently, pharmacological activation of Sur1/Kir6.2 function could alleviate experimental pulmonary hypertension. Methods and Results: We demonstrated that SUR1 and Kir6.2 expressions are not significantly altered in lung and PA from human PAH or experimental model of PAH. In contrast, SUR1 and Kir6.2 expressions are strongly reduced in right ventricular tissues from MCT rats. Using myograph experiments on isolated PA we showed that pharmacological activation of this channels by diazoxide leads to PA relaxation. Moreover, the pharmacological inhibition of this channels by nateglinide 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 significantly prevented MCT-induced PH in rats. Additionally, in vivo short term administration of diazoxide improved cardiac output and pulmonary vascular resistance. Conclusions: In PAH and experimental PH, SUR1/Kir6.2 expressions are th.e sa.me as in controls. In vivo long term pharmacological activation of the channel alleviated MCT-induced PH. These results show that this channel should be considered as a new therapeutic target.