PCSK9 inhibitor alleviates experimental pulmonary fibrosis-induced pulmonary hypertension via attenuating epithelial-mesenchymal transition by suppressing Wnt/β-catenin signaling in vivo and in vitro
BackgroundThe co-occurrence of pulmonary hypertension (PH) in patients with pulmonary fibrosis (PF) is linked to a more unfavorable prognosis and increased mortality compared to PF cases without PH. Early intervention and comprehensive management are pivotal for improving survival outcomes. Proprote...
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Frontiers Media S.A.
2024-12-01
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| Series: | Frontiers in Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmed.2024.1509168/full |
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| author | Jiancheng Lin Jiancheng Lin Jiancheng Lin Zetao Pan Zetao Pan Zetao Pan Jiayan Sun Jiayan Sun Jiayan Sun Xiaowan Wang Xiaowan Wang Xiaowan Wang Di Yin Di Yin Di Yin Cunyang Huo Cunyang Huo Cunyang Huo Qiang Guo Qiang Guo Qiang Guo Qiang Guo |
| author_facet | Jiancheng Lin Jiancheng Lin Jiancheng Lin Zetao Pan Zetao Pan Zetao Pan Jiayan Sun Jiayan Sun Jiayan Sun Xiaowan Wang Xiaowan Wang Xiaowan Wang Di Yin Di Yin Di Yin Cunyang Huo Cunyang Huo Cunyang Huo Qiang Guo Qiang Guo Qiang Guo Qiang Guo |
| author_sort | Jiancheng Lin |
| collection | DOAJ |
| description | BackgroundThe co-occurrence of pulmonary hypertension (PH) in patients with pulmonary fibrosis (PF) is linked to a more unfavorable prognosis and increased mortality compared to PF cases without PH. Early intervention and comprehensive management are pivotal for improving survival outcomes. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein essential in cholesterol metabolism. However, the potential for PCSK9 inhibition to alleviate PF-induced PH has not been previously reported.MethodsA mouse model of PF-induced PH was established using intratracheal injection of bleomycin (BLM), followed by administration of a PCSK9 inhibitor every other day. Data on right ventricle (RV) remodeling and changes in pulmonary arteries were collected and analyzed. Transforming growth factor-beta (TGF-β) was also administered to MLE-12 cells as an experimental lung fibrosis model. The mechanisms of PCSK9’s impact on lung fibrosis were examined both in vivo and in vitro.ResultsInhibition of PCSK9 significantly reduced pulmonary artery thickening and RV remodeling in the BLM-induced mouse model. Moreover, the blockage of PCSK9 effectively attenuated the migration and epithelial-mesenchymal transition (EMT) process of TGF-β-induced MLE-12 cells. We also observed that the PCSK9 inhibitor suppressed the expression of the Wnt/β-catenin pathway in both animal and cell experiments.ConclusionPCSK9 plays a crucial role in the progression of PF-induced PH by regulating cell EMT and Wnt/β-catenin signaling. Targeting PCSK9 expression or activity could effectively control lung fibrosis and its PH complication. |
| format | Article |
| id | doaj-art-5260c70cb15f43b888fac1ccbc9df3f5 |
| institution | DOAJ |
| issn | 2296-858X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Medicine |
| spelling | doaj-art-5260c70cb15f43b888fac1ccbc9df3f52025-08-20T02:49:57ZengFrontiers Media S.A.Frontiers in Medicine2296-858X2024-12-011110.3389/fmed.2024.15091681509168PCSK9 inhibitor alleviates experimental pulmonary fibrosis-induced pulmonary hypertension via attenuating epithelial-mesenchymal transition by suppressing Wnt/β-catenin signaling in vivo and in vitroJiancheng Lin0Jiancheng Lin1Jiancheng Lin2Zetao Pan3Zetao Pan4Zetao Pan5Jiayan Sun6Jiayan Sun7Jiayan Sun8Xiaowan Wang9Xiaowan Wang10Xiaowan Wang11Di Yin12Di Yin13Di Yin14Cunyang Huo15Cunyang Huo16Cunyang Huo17Qiang Guo18Qiang Guo19Qiang Guo20Qiang Guo21Medical College of Soochow University, Suzhou, Jiangsu, ChinaDepartment of Emergency and Critical Care Medicine, The Fourth Affiliated Hospital of Soochow University (Suzhou Dushu Lake Hospital), Suzhou, Jiangsu, ChinaMedical Center of Soochow University, Suzhou, Jiangsu, ChinaMedical College of Soochow University, Suzhou, Jiangsu, ChinaDepartment of Emergency and Critical Care Medicine, The Fourth Affiliated Hospital of Soochow University (Suzhou Dushu Lake Hospital), Suzhou, Jiangsu, ChinaMedical Center of Soochow University, Suzhou, Jiangsu, ChinaMedical College of Soochow University, Suzhou, Jiangsu, ChinaDepartment of Emergency and Critical Care Medicine, The Fourth Affiliated Hospital of Soochow University (Suzhou Dushu Lake Hospital), Suzhou, Jiangsu, ChinaMedical Center of Soochow University, Suzhou, Jiangsu, ChinaMedical College of Soochow University, Suzhou, Jiangsu, ChinaDepartment of Emergency and Critical Care Medicine, The Fourth Affiliated Hospital of Soochow University (Suzhou Dushu Lake Hospital), Suzhou, Jiangsu, ChinaMedical Center of Soochow University, Suzhou, Jiangsu, ChinaMedical College of Soochow University, Suzhou, Jiangsu, ChinaDepartment of Emergency and Critical Care Medicine, The Fourth Affiliated Hospital of Soochow University (Suzhou Dushu Lake Hospital), Suzhou, Jiangsu, ChinaMedical Center of Soochow University, Suzhou, Jiangsu, ChinaMedical College of Soochow University, Suzhou, Jiangsu, ChinaDepartment of Emergency and Critical Care Medicine, The Fourth Affiliated Hospital of Soochow University (Suzhou Dushu Lake Hospital), Suzhou, Jiangsu, ChinaMedical Center of Soochow University, Suzhou, Jiangsu, ChinaMedical College of Soochow University, Suzhou, Jiangsu, ChinaDepartment of Emergency and Critical Care Medicine, The Fourth Affiliated Hospital of Soochow University (Suzhou Dushu Lake Hospital), Suzhou, Jiangsu, ChinaMedical Center of Soochow University, Suzhou, Jiangsu, ChinaThe First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, ChinaBackgroundThe co-occurrence of pulmonary hypertension (PH) in patients with pulmonary fibrosis (PF) is linked to a more unfavorable prognosis and increased mortality compared to PF cases without PH. Early intervention and comprehensive management are pivotal for improving survival outcomes. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein essential in cholesterol metabolism. However, the potential for PCSK9 inhibition to alleviate PF-induced PH has not been previously reported.MethodsA mouse model of PF-induced PH was established using intratracheal injection of bleomycin (BLM), followed by administration of a PCSK9 inhibitor every other day. Data on right ventricle (RV) remodeling and changes in pulmonary arteries were collected and analyzed. Transforming growth factor-beta (TGF-β) was also administered to MLE-12 cells as an experimental lung fibrosis model. The mechanisms of PCSK9’s impact on lung fibrosis were examined both in vivo and in vitro.ResultsInhibition of PCSK9 significantly reduced pulmonary artery thickening and RV remodeling in the BLM-induced mouse model. Moreover, the blockage of PCSK9 effectively attenuated the migration and epithelial-mesenchymal transition (EMT) process of TGF-β-induced MLE-12 cells. We also observed that the PCSK9 inhibitor suppressed the expression of the Wnt/β-catenin pathway in both animal and cell experiments.ConclusionPCSK9 plays a crucial role in the progression of PF-induced PH by regulating cell EMT and Wnt/β-catenin signaling. Targeting PCSK9 expression or activity could effectively control lung fibrosis and its PH complication.https://www.frontiersin.org/articles/10.3389/fmed.2024.1509168/fullpulmonary fibrosispulmonary hypertensionPCSK9EMTWntβ-catenin |
| spellingShingle | Jiancheng Lin Jiancheng Lin Jiancheng Lin Zetao Pan Zetao Pan Zetao Pan Jiayan Sun Jiayan Sun Jiayan Sun Xiaowan Wang Xiaowan Wang Xiaowan Wang Di Yin Di Yin Di Yin Cunyang Huo Cunyang Huo Cunyang Huo Qiang Guo Qiang Guo Qiang Guo Qiang Guo PCSK9 inhibitor alleviates experimental pulmonary fibrosis-induced pulmonary hypertension via attenuating epithelial-mesenchymal transition by suppressing Wnt/β-catenin signaling in vivo and in vitro Frontiers in Medicine pulmonary fibrosis pulmonary hypertension PCSK9 EMT Wnt β-catenin |
| title | PCSK9 inhibitor alleviates experimental pulmonary fibrosis-induced pulmonary hypertension via attenuating epithelial-mesenchymal transition by suppressing Wnt/β-catenin signaling in vivo and in vitro |
| title_full | PCSK9 inhibitor alleviates experimental pulmonary fibrosis-induced pulmonary hypertension via attenuating epithelial-mesenchymal transition by suppressing Wnt/β-catenin signaling in vivo and in vitro |
| title_fullStr | PCSK9 inhibitor alleviates experimental pulmonary fibrosis-induced pulmonary hypertension via attenuating epithelial-mesenchymal transition by suppressing Wnt/β-catenin signaling in vivo and in vitro |
| title_full_unstemmed | PCSK9 inhibitor alleviates experimental pulmonary fibrosis-induced pulmonary hypertension via attenuating epithelial-mesenchymal transition by suppressing Wnt/β-catenin signaling in vivo and in vitro |
| title_short | PCSK9 inhibitor alleviates experimental pulmonary fibrosis-induced pulmonary hypertension via attenuating epithelial-mesenchymal transition by suppressing Wnt/β-catenin signaling in vivo and in vitro |
| title_sort | pcsk9 inhibitor alleviates experimental pulmonary fibrosis induced pulmonary hypertension via attenuating epithelial mesenchymal transition by suppressing wnt β catenin signaling in vivo and in vitro |
| topic | pulmonary fibrosis pulmonary hypertension PCSK9 EMT Wnt β-catenin |
| url | https://www.frontiersin.org/articles/10.3389/fmed.2024.1509168/full |
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