Abstract 10523: Involvement of Sur2/Kir6.1 In the Physiopathology of Pulmonary Arterial Hypertension

Abstract

Introduction: The ATP-sensitive K+ channels (KATP) regulatory subunit ABCC8 may be considered a new therapeutic target for pulmonary arterial hypertension (PAH). Hypothesis: We hypothesised that the second KATP regulatory subunit (ABCC9) contributes to PAH pathogenesis. ABCC9 gene encodes for two regulatory subunits of KATP channels: the SUR2A and SURB proteins. In the KATP channel, the SUR2 subunits are associated with the K+ channel Kir6.1. We investigated how the SUR2/Kir6.1 channel contributes to PAH pathogenesis and its potential as a therapeutic target against PAH. Methods: Using in vitro, ex vivo, and in vivo approaches, we analysed the localisation and expression of SUR2A, SUR2B, and Kir6.1 in pulmonary vasculature of controls and patients with PAH as in experimental PH rat models and its contribution to PAH physiopathology. Finally, we deciphered the consequences of in vivo activation of SUR2/Kir6.1 in the monocrotaline (MCT)-induced PH model. Results: We demonstrated that SUR2A, SUR2B, and Kir6.1 were expressed in the lungs of controls and patients with PAH and MCT-induced PH rat model. Myograph experiments showed that activation of SUR2 by pinacidil induced pulmonary arterial relaxation. In vitro experiments on human pulmonary arterial smooth muscle cells and endothelial cells (hPASMCs and hPAECs) in controls and PAH patients showed decreased cell proliferation and migration after SUR2 activation. Using patch-clamp, we demonstrated that SUR2 activation in rat right ventricular (RV) cardiomyocytes reduced RV action potential duration. Chronic pinacidil administration in control rats increased heart rate without changes in hemodynamic parameters. Finally, in vivo pharmacological activation of SUR2 on MCT-induced-PH rats showed an improvement of PH during the preventive and curative protocol. Conclusions: We demonstrated that SUR2A, SUR2B, and Kir6.1 were expressed in hPASMCs and hPAECs of controls and PAH patients. In vivo SUR2 activation reduced MCT-induced PH phenotype, suggesting that SUR2 activation should be considered for treatment of PAH.