Le Ribeuz Hélène, Masson Bastien, Dutheil Mary, Boët Angèle, Beauvais Antoine, Sabourin Jessica, De Montpreville Vincent Thomas, Capuano Véronique, Mercier Olaf, Humbert Marc, Montani David, Antigny Fabrice
Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France.
INSERM UMR_S 999 « Hypertension Pulmonaire Physiopathologie et Innovation Thérapeutique », Hôpital Marie Lannelongue, Le Plessis-Robinson, France.
Front Cardiovasc Med. 2023 Jan 10;9:1066047. doi: 10.3389/fcvm.2022.1066047. eCollection 2022.
We hypothesized that the ATP-sensitive K channels (KATP) regulatory subunit (ABCC9) contributes to PAH pathogenesis. gene encodes for two regulatory subunits of KATP channels: the SUR2A and SUR2B 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 in PAH.
Using , and approaches, we analyzed the localization and expression of SUR2A, SUR2B, and Kir6.1 in the pulmonary vasculature of controls and patients with PAH as in experimental pulmonary hypertension (PH) rat models and its contribution to PAH physiopathology. Finally, we deciphered the consequences of activation of SUR2/Kir6.1 in the monocrotaline (MCT)-induced PH model. We found that SUR2A, SUR2B, and Kir6.1 were expressed in the lungs of controls and patients with PAH and MCT-induced PH rat models. Organ bath studies showed that SUR2 activation by pinacidil induced relaxation of pulmonary arterial in rats and humans. 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. We demonstrated that SUR2 activation in rat right ventricular (RV) cardiomyocytes reduced RV action potential duration by patch-clamp. Chronic pinacidil administration in control rats increased heart rate without changes in hemodynamic parameters. Finally, pharmacological activation of SUR2 on MCT and Chronic-hypoxia (CH)-induced-PH rats showed improved PH.
We showed that SUR2A, SUR2B, and Kir6.1 are presented in hPASMCs and hPAECs of controls and PAH patients. SUR2 activation reduced the MCT-induced and CH-induced PH phenotype, suggesting that SUR2 activation should be considered for treating PAH.
我们推测ATP敏感性钾通道（KATP）调节亚基（ABCC9）与肺动脉高压（PAH）的发病机制有关。该基因编码KATP通道的两个调节亚基：SUR2A和SUR2B蛋白。在KATP通道中，SUR2亚基与钾通道Kir6.1相关联。我们研究了SUR2/Kir6.1通道如何促成PAH的发病机制及其作为PAH治疗靶点的潜力。
使用[具体方法1]、[具体方法2]和[具体方法3]方法，我们分析了对照组以及PAH患者的肺血管中SUR2A、SUR2B和Kir6.1的定位和表达，如同在实验性肺动脉高压（PH）大鼠模型中一样，并分析了其对PAH病理生理学的影响。最后，我们在野百合碱（MCT）诱导的PH模型中解读了SUR2/Kir6.1激活的后果。我们发现SUR2A、SUR2B和Kir6.1在对照组、PAH患者以及MCT诱导的PH大鼠模型的肺中均有表达。器官浴研究表明，吡那地尔激活SUR2可诱导大鼠和人类肺动脉舒张。对对照组和PAH患者的人肺动脉平滑肌细胞和内皮细胞（hPASMCs和hPAECs）进行的[具体实验]表明，SUR2激活后细胞增殖和迁移减少。我们通过膜片钳技术证明，大鼠右心室（RV）心肌细胞中SUR2激活可缩短RV动作电位时程。对照大鼠长期给予吡那地尔可增加心率，但血流动力学参数无变化。最后，对MCT和慢性低氧（CH）诱导的PH大鼠进行SUR2的药理学激活显示PH有所改善。
我们表明，SUR2A、SUR2B和Kir6.1存在于对照组和PAH患者的hPASMCs和hPAECs中。SUR2激活减轻了MCT诱导和CH诱导的PH表型，提示SUR2激活可作为PAH治疗的一种选择。
