Rôle des canaux potassiques KCNK3/TASK-1 et KATP dans la pathogenèse de l'hypertension artérielle pulmonaire

Pulmonary arterial hypertension (PAH) is a devastating cause of PH due to a progressive narrowing of the distal pulmonary arteries (<500 µm in diameter) resulting in high pulmonary vascular resistance and right heart failure. To date, about twenty genes have been described as mutated in PAH patients, among them there are two potassium channels: KCNK3 and ABCC8. It has been shown that mutations in KCNK3 gene lead to a loss of function of the channel. Moreover, our team demonstrated that this loss of KCNK3 is a hallmark of PAH development since it was found in several PAH forms as well as in animal models of PH. During my thesis, i was interested in highlighting the implication of the loss of function of KCNK3 by performing proteomic analysis in PASMCs and PAECs treated with a si KCNK3 compared to the si Control. This analysis allow us to highlight several signalling pathways and biological pathways deregulated by KCNK3 loss of function. On the other hand, the discovery in 2018 in PAH patients of mutations on ABCC8 gene coding for the SUR1 subunit of the KATP Sur1/Kir6.2 potassium channel led us to study this channel in the pathophysiology of PAH. Through in-vitro, ex-vivo and in-vivo experiments, we have highlighted the therapeutic interest of SUR1 in PAH. Finally, we also wanted to determine the role of the KATP Sur2/Kir6.1 which share a great homology with SUR1/Kir6.2. Our study on this channel allowed us to demonstrate that the activation of this channel in the pulmonary vascular system could attenuate the development of PAH.L'hypertension artérielle pulmonaire (HTAP) est une maladie cardio-pulmonaire dévastatrice due à une obstruction progressive des artères pulmonaires distales (