Angiotensin-converting enzyme 2 activation suppresses pulmonary vascular remodeling by inducing apoptosis through the Hippo signaling pathway in rats with pulmonary arterial hypertension
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 mo...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2019-08-01
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| Series: | Clinical and Experimental Hypertension |
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| Online Access: | http://dx.doi.org/10.1080/10641963.2019.1583247 |
| _version_ | 1827814287324741632 |
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| author | Daole Yan Gang Li Yaozhong Zhang Yinglong Liu |
| author_facet | Daole Yan Gang Li Yaozhong Zhang Yinglong Liu |
| author_sort | Daole Yan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T23:43:25Z |
| format | Article |
| id | doaj.art-e2ecd5ed3fb74291a25a14be58210c7b |
| institution | Directory Open Access Journal |
| issn | 1064-1963 1525-6006 |
| language | English |
| last_indexed | 2024-03-11T23:43:25Z |
| publishDate | 2019-08-01 |
| publisher | Taylor & Francis Group |
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| series | Clinical and Experimental Hypertension |
| spelling | doaj.art-e2ecd5ed3fb74291a25a14be58210c7b2023-09-19T15:19:28ZengTaylor & Francis GroupClinical and Experimental Hypertension1064-19631525-60062019-08-0141658959810.1080/10641963.2019.15832471583247Angiotensin-converting enzyme 2 activation suppresses pulmonary vascular remodeling by inducing apoptosis through the Hippo signaling pathway in rats with pulmonary arterial hypertensionDaole Yan0Gang Li1Yaozhong Zhang2Yinglong Liu3Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel DiseasesBeijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel DiseasesBeijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel DiseasesBeijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel DiseasesObjective: 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.http://dx.doi.org/10.1080/10641963.2019.1583247ace2pahhippoapoptosisvascular remodeling |
| spellingShingle | Daole Yan Gang Li Yaozhong Zhang Yinglong Liu 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 ace2 pah hippo apoptosis vascular remodeling |
| title | Angiotensin-converting enzyme 2 activation suppresses pulmonary vascular remodeling by inducing apoptosis through the Hippo signaling pathway in rats with pulmonary arterial hypertension |
| title_full | Angiotensin-converting enzyme 2 activation suppresses pulmonary vascular remodeling by inducing apoptosis through the Hippo signaling pathway in rats with pulmonary arterial hypertension |
| title_fullStr | Angiotensin-converting enzyme 2 activation suppresses pulmonary vascular remodeling by inducing apoptosis through the Hippo signaling pathway in rats with pulmonary arterial hypertension |
| title_full_unstemmed | Angiotensin-converting enzyme 2 activation suppresses pulmonary vascular remodeling by inducing apoptosis through the Hippo signaling pathway in rats with pulmonary arterial hypertension |
| title_short | Angiotensin-converting enzyme 2 activation suppresses pulmonary vascular remodeling by inducing apoptosis through the Hippo signaling pathway in rats with pulmonary arterial hypertension |
| title_sort | angiotensin converting enzyme 2 activation suppresses pulmonary vascular remodeling by inducing apoptosis through the hippo signaling pathway in rats with pulmonary arterial hypertension |
| topic | ace2 pah hippo apoptosis vascular remodeling |
| url | http://dx.doi.org/10.1080/10641963.2019.1583247 |
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