Angiotensin-converting enzyme 2 activation suppresses pulmonary vascular remodeling by inducing apoptosis through the Hippo signaling pathway in rats with pulmonary arterial hypertension
机构：[1]Pediatric Cardiac Center, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China临床科室小儿心脏中心首都医科大学附属安贞医院
Objective: To investigate the effects of angiotensin-converting enzyme 2 (ACE2) activation on pulmonary arterial cell apoptosis during pulmonary vascular remodeling associated with pulmonary arterial hypertension (PAH) and to elucidate potential mechanisms related to Hippo signaling. Methods: PAH model was developed by injecting monocrotaline combined with left pneumonectomy using Sprague-Dawley rat. Then, resorcinolnaphthalein (Res; ACE2 activator), MLN-4760 (ACE2 inhibitor), A-779 (Mas inhibitor), and 4-((5,10-dimethyl-6-oxo-6,10-dihydro-5H-pyrimido[5,4-b]thieno[3,2-e][1,4]diazepin-2-yl)amino) benzenesulfonamide (XMU-MP-1; MST1/2 inhibitor) were administered via continuous subcutaneous or intraperitoneal injection for 3 weeks. Animals were randomly divided into six groups: control, PAH, PAH+Res, PAH+Res+MLN-4760, PAH+Res+A-779, and PAH+Res+XMU-MP-1. On 21 day, hemodynamics and pathologic lesions were evaluated. Apoptosis and apoptosis-associated proteins were detected by TUNEL and western blotting. ACE2 activity and Hippo pathway components including large tumor suppressor 1 (LATS1), Yes-associated protein (Yap), and phosphorylated Yap (p-Yap) were investigated by fluorogenic peptide assays and western blotting. Results: In the PAH models, the mean pulmonary arterial pressure, right ventricular hypertrophy index, pulmonary vascular remodeling, anti-apoptotic protein Bcl-2 and Yap were all increased but the pulmonary arterial cell apoptosis, pro-apoptotic proteins caspase-3 and Bax were lower. ACE2 activation significantly ameliorated pulmonary arterial remodeling, this action was related to increased apoptosis and up-regulation of LATS1 and p-Yap. These protective effects were mitigated by the co-administration of A779 or MLN-4760. Moreover, inhibiting the Hippo/LATS1/Yap pathway with XMU-MP-1 blocked apoptosis in pulmonary vascular cells induced by ACE2 activation during the prevention of PAH. Conclusions: Our findings suggest that ACE2 activation attenuates pulmonary vascular remodeling by inducing pulmonary arterial cell apoptosis via Hippo/Yap signaling during the development of PAH.
基金：
National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81570443, 81600383]; Beijing Natural Science FoundationBeijing Natural Science Foundation [7164252]; Beijing Municipal Administration of Hospitals [QML20170601]
第一作者机构：[1]Pediatric Cardiac Center, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China
通讯作者：
通讯机构：[1]Pediatric Cardiac Center, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China[*1]Pediatric Cardiac Center, Beijing Anzhen Hospital of Capital Medical University, 2 Anzhen Road, Chao yang, Beijing 100029, P.R. China
推荐引用方式(GB/T 7714)：
Daole Yan,Gang Li,Yaozhong Zhang,et al.Angiotensin-converting enzyme 2 activation suppresses pulmonary vascular remodeling by inducing apoptosis through the Hippo signaling pathway in rats with pulmonary arterial hypertension[J].CLINICAL AND EXPERIMENTAL HYPERTENSION.2019,41(6):589-598.doi:10.1080/10641963.2019.1583247.
APA：
Daole Yan,Gang Li,Yaozhong Zhang&Yinglong Liu.(2019).Angiotensin-converting enzyme 2 activation suppresses pulmonary vascular remodeling by inducing apoptosis through the Hippo signaling pathway in rats with pulmonary arterial hypertension.CLINICAL AND EXPERIMENTAL HYPERTENSION,41,(6)
MLA：
Daole Yan,et al."Angiotensin-converting enzyme 2 activation suppresses pulmonary vascular remodeling by inducing apoptosis through the Hippo signaling pathway in rats with pulmonary arterial hypertension".CLINICAL AND EXPERIMENTAL HYPERTENSION 41..6(2019):589-598
