Abstract 9511: Implication of the KATP SUR2B/kir6.1 in the Physiopathology of Pulmonary Arterial Hypertension

Abstract

Introduction: PAH is a severe and rare cardiopulmonary disease which is defined by an elevation of the mean pulmonary artery pressure >25mmHg. ABCC9 mutations are responsible of Cantu syndrome, a disease characterised by several cardiac disorders and for some case pulmonary hypertension (PH). ABCC9 gene encodes for SUR2 protein, a regulatory subunit of KATP channels. KATP are composed of SUR1 or SUR2 and Kir6.1 or Kir6.2 subunits. We hypothesized that SUR2 / Kir6.1 channel contributes to PAH pathogenesis and could be a therapeutic target against PAH. Methods: Using a combination of in vitro , ex vivo and in vivo approaches, we analysed the localisation and expression of SUR2A, SUR2B and Kir6.1 in pulmonary vasculature from control and PAH patients as well as in experimental PH rat-models. We also analysed the role of SUR2/Kir6.1 in PAH physiopathology (PASMCs proliferation, migration and contraction). Finally, we deciphered the consequences of in vivo pharmacological activation of SUR2/Kir6.1 in experimental model of PH. Results: We demonstrated that SUR2A, SUR2B and Kir6.1 are expressed (mRNA and protein) in lungs from control and PAH patients and in MCT induced-PH model.Myograph experiments demonstrated that pharmacological activation of SUR2 by pinacidil 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 (hPASMCs) from control and PAH patients show a decrease of the cell proliferation and migration after SUR2 activation (pinacidil). Using Patch-clamp technique, we demonstrated that SUR2 activator (pinacidil) in adult rat RV cardiomyocytes reduces RV action potential. Finally, pharmacological activation in vivo of SUR2 by pinacidil (1mg/kg/day) on MCT induced-PH rats show an improvement of the hemodynamic parameters as the mean right ventricular systolic pressure during preventive and curative protocol. Conclusions: We demonstrated that SUR2A, SUR2B and Kir6.1 are expressed in hPASMCs and hPECs from control and iPAH patients. The in vivo SUR2 activation by pinacidil treatment reduced MCT induced-PH phenotype suggesting that SUR2 pharmacological activation should be considered for PAH.