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

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.

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.

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.

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.