Overexpressed pigment epithelium-derived factor alleviates pulmonary hypertension in two rat models induced by monocrotaline and SU5416/hypoxia
Background: Pulmonary hypertension (PH) is a progressive and fatal cardiopulmonary disease characterized by vascular remodeling and is associated with endothelial-to-mesenchymal transition (EndoMT). The pigment epithelium-derived factor (PEDF), a secretory protein widely distributed in multiple orga...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-03-01
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| Series: | Biomedicine & Pharmacotherapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332224001847 |
| _version_ | 1797291872963526656 |
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| author | Haoran Miao Hongliang Hui Wenbin Fan Yangui Lin Huaming Li Dan Li Min Luo Fan Qiu Bo Jiang Yiqian Zhang |
| author_facet | Haoran Miao Hongliang Hui Wenbin Fan Yangui Lin Huaming Li Dan Li Min Luo Fan Qiu Bo Jiang Yiqian Zhang |
| author_sort | Haoran Miao |
| collection | DOAJ |
| description | Background: Pulmonary hypertension (PH) is a progressive and fatal cardiopulmonary disease characterized by vascular remodeling and is associated with endothelial-to-mesenchymal transition (EndoMT). The pigment epithelium-derived factor (PEDF), a secretory protein widely distributed in multiple organs, has been shown to demonstrate anti-EndoMT activity in cardiovascular diseases. In the present study, the role of PEDF in PH was investigated. Methods: For PEDF overexpression, Sprague Dawley rats were infected with an adeno-associated virus through injection via the internal jugular vein. To establish PH models, the animals were subjected to monocrotaline or Sugen/hypoxia. Four weeks later, pulmonary artery angiography was performed, and hemodynamic parameters, right ventricular function, and vascular remodeling were evaluated. EndoMT and cell proliferation in the pulmonary arteries were assessed via immunofluorescence staining. Moreover, pulmonary artery endothelial cells (PAECs) isolated from experimental PH rats were cultured to investigate the underlying molecular mechanisms involved. Results: PEDF expression was significantly downregulated in PAECs from PH patients and PH model rats. Overexpressed PEDF alleviated the development of PH by improving pulmonary artery morphology and perfusion, reducing pulmonary artery pressure, improving right ventricular function, and alleviating vascular remodeling. PEDF inhibits EndoMT and reduces excessive PAEC proliferation. Moreover, PEDF overexpression reduced EndoMT in cultured PAECs by competitively inhibiting the binding of wnt to LRP6 and downregulating phosphorylation at the 1490 site of LRP6. Conclusions: Our findings suggest that PEDF may be a potential therapeutic target for PH. We also found that PEDF can inhibit EndoMT in PAECs and may exert these effects by inhibiting the Wnt/LRP6/β-catenin pathway. |
| first_indexed | 2024-03-07T19:43:04Z |
| format | Article |
| id | doaj.art-fcf3a52ceef4417eb07c126bb37ab403 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-07T19:43:04Z |
| publishDate | 2024-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-fcf3a52ceef4417eb07c126bb37ab4032024-02-29T05:18:01ZengElsevierBiomedicine & Pharmacotherapy0753-33222024-03-01172116303Overexpressed pigment epithelium-derived factor alleviates pulmonary hypertension in two rat models induced by monocrotaline and SU5416/hypoxiaHaoran Miao0Hongliang Hui1Wenbin Fan2Yangui Lin3Huaming Li4Dan Li5Min Luo6Fan Qiu7Bo Jiang8Yiqian Zhang9Department of Thoracic Cardiovascular Surgery, ChinaDepartment of Thoracic Cardiovascular Surgery, ChinaDepartment of Thoracic Cardiovascular Surgery, ChinaDepartment of Thoracic Cardiovascular Surgery, ChinaDepartment of Thoracic Cardiovascular Surgery, ChinaCommunity Health Center, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, ChinaDepartment of Thoracic Cardiovascular Surgery, ChinaDepartment of Thoracic Cardiovascular Surgery, China; Correspondence to: Department of Thoracic Cardiovascular Surgery, The Eighth Affiliated Hospital of Sun Yat-sen University, 3025 Shennan Middle Road, Shenzhen, Guangdong 518033, China.Department of Thoracic Cardiovascular Surgery, China; Correspondence to: Department of Thoracic Cardiovascular Surgery, The Eighth Affiliated Hospital of Sun Yat-sen University, 3025 Shennan Middle Road, Shenzhen, Guangdong 518033, China.Department of Thoracic Cardiovascular Surgery, China; Correspondence to: Department of Thoracic Cardiovascular Surgery, The Eighth Affiliated Hospital of Sun Yat-sen University, 3025 Shennan Middle Road, Shenzhen, Guangdong 518033, China.Background: Pulmonary hypertension (PH) is a progressive and fatal cardiopulmonary disease characterized by vascular remodeling and is associated with endothelial-to-mesenchymal transition (EndoMT). The pigment epithelium-derived factor (PEDF), a secretory protein widely distributed in multiple organs, has been shown to demonstrate anti-EndoMT activity in cardiovascular diseases. In the present study, the role of PEDF in PH was investigated. Methods: For PEDF overexpression, Sprague Dawley rats were infected with an adeno-associated virus through injection via the internal jugular vein. To establish PH models, the animals were subjected to monocrotaline or Sugen/hypoxia. Four weeks later, pulmonary artery angiography was performed, and hemodynamic parameters, right ventricular function, and vascular remodeling were evaluated. EndoMT and cell proliferation in the pulmonary arteries were assessed via immunofluorescence staining. Moreover, pulmonary artery endothelial cells (PAECs) isolated from experimental PH rats were cultured to investigate the underlying molecular mechanisms involved. Results: PEDF expression was significantly downregulated in PAECs from PH patients and PH model rats. Overexpressed PEDF alleviated the development of PH by improving pulmonary artery morphology and perfusion, reducing pulmonary artery pressure, improving right ventricular function, and alleviating vascular remodeling. PEDF inhibits EndoMT and reduces excessive PAEC proliferation. Moreover, PEDF overexpression reduced EndoMT in cultured PAECs by competitively inhibiting the binding of wnt to LRP6 and downregulating phosphorylation at the 1490 site of LRP6. Conclusions: Our findings suggest that PEDF may be a potential therapeutic target for PH. We also found that PEDF can inhibit EndoMT in PAECs and may exert these effects by inhibiting the Wnt/LRP6/β-catenin pathway.http://www.sciencedirect.com/science/article/pii/S0753332224001847Pigment epithelium-derived factorPulmonary hypertensionVascular remodelingEndothelial-to-mesenchymal transition |
| spellingShingle | Haoran Miao Hongliang Hui Wenbin Fan Yangui Lin Huaming Li Dan Li Min Luo Fan Qiu Bo Jiang Yiqian Zhang Overexpressed pigment epithelium-derived factor alleviates pulmonary hypertension in two rat models induced by monocrotaline and SU5416/hypoxia Biomedicine & Pharmacotherapy Pigment epithelium-derived factor Pulmonary hypertension Vascular remodeling Endothelial-to-mesenchymal transition |
| title | Overexpressed pigment epithelium-derived factor alleviates pulmonary hypertension in two rat models induced by monocrotaline and SU5416/hypoxia |
| title_full | Overexpressed pigment epithelium-derived factor alleviates pulmonary hypertension in two rat models induced by monocrotaline and SU5416/hypoxia |
| title_fullStr | Overexpressed pigment epithelium-derived factor alleviates pulmonary hypertension in two rat models induced by monocrotaline and SU5416/hypoxia |
| title_full_unstemmed | Overexpressed pigment epithelium-derived factor alleviates pulmonary hypertension in two rat models induced by monocrotaline and SU5416/hypoxia |
| title_short | Overexpressed pigment epithelium-derived factor alleviates pulmonary hypertension in two rat models induced by monocrotaline and SU5416/hypoxia |
| title_sort | overexpressed pigment epithelium derived factor alleviates pulmonary hypertension in two rat models induced by monocrotaline and su5416 hypoxia |
| topic | Pigment epithelium-derived factor Pulmonary hypertension Vascular remodeling Endothelial-to-mesenchymal transition |
| url | http://www.sciencedirect.com/science/article/pii/S0753332224001847 |
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