SphK1/S1P mediates TGF-β1-induced proliferation of pulmonary artery smooth muscle cells and its potential mechanisms
The upregulation of Sphingosine kinase 1 (SphK1) expression and accompanied sphingosine-1-phosphate (S1P) production have been reported to contribute to the proliferation of pulmonary artery smooth muscle cells (PASMC) and pulmonary arterial remodeling. However, the molecular mechanisms of SphK1/S1P...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2018-12-01
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| Series: | Pulmonary Circulation |
| Online Access: | https://doi.org/10.1177/2045894018816977 |
| _version_ | 1818548498386124800 |
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| author | Jian Wang Wei Feng Fangwei Li Wenhua Shi Cui Zhai Shaojun Li Yanting Zhu Xin Yan Qingting Wang Lu Liu Xinming Xie Manxiang Li |
| author_facet | Jian Wang Wei Feng Fangwei Li Wenhua Shi Cui Zhai Shaojun Li Yanting Zhu Xin Yan Qingting Wang Lu Liu Xinming Xie Manxiang Li |
| author_sort | Jian Wang |
| collection | DOAJ |
| description | The upregulation of Sphingosine kinase 1 (SphK1) expression and accompanied sphingosine-1-phosphate (S1P) production have been reported to contribute to the proliferation of pulmonary artery smooth muscle cells (PASMC) and pulmonary arterial remodeling. However, the molecular mechanisms of SphK1/S1P upregulation in PASMC and the specific mechanisms of how SphK1/S1P pathway promotes PASMC proliferation remain largely unclear. This study aims to address these issues. Here, we demonstrated that TGF-β1 significantly upregulated SphK1 expression and S1P production by promoting the phosphorylation of Smad2/3 in PASMC. Further study indicated that SphK1/S1P pathway mediated TGF-β1-induced Notch3 activation in PASMC. In addition, we showed that TGF-β1 significantly induced proliferation of PASMC, while pre-inhibition of Smad2/3 phosphorylation with SB431542 or silencing SphK1 using small interfering RNA in advance, or pre-blocking Notch3 pathway with N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), attenuated TGF-β1-induced PASMC proliferation. Taken together, our study indicates that Smad2/3/SphK1/S1P/Notch3 pathway mediates TGF-β1-induced PASMC proliferation and suggests this pathway as a potential therapeutic target in the prevention and treatment of pulmonary hypertension. |
| first_indexed | 2024-12-12T08:20:45Z |
| format | Article |
| id | doaj.art-43a869c47ebb4dd4bb2f1039f2eb27ae |
| institution | Directory Open Access Journal |
| issn | 2045-8940 |
| language | English |
| last_indexed | 2024-12-12T08:20:45Z |
| publishDate | 2018-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Pulmonary Circulation |
| spelling | doaj.art-43a869c47ebb4dd4bb2f1039f2eb27ae2022-12-22T00:31:24ZengWileyPulmonary Circulation2045-89402018-12-01910.1177/2045894018816977SphK1/S1P mediates TGF-β1-induced proliferation of pulmonary artery smooth muscle cells and its potential mechanismsJian WangWei FengFangwei LiWenhua ShiCui ZhaiShaojun LiYanting ZhuXin YanQingting WangLu LiuXinming XieManxiang LiThe upregulation of Sphingosine kinase 1 (SphK1) expression and accompanied sphingosine-1-phosphate (S1P) production have been reported to contribute to the proliferation of pulmonary artery smooth muscle cells (PASMC) and pulmonary arterial remodeling. However, the molecular mechanisms of SphK1/S1P upregulation in PASMC and the specific mechanisms of how SphK1/S1P pathway promotes PASMC proliferation remain largely unclear. This study aims to address these issues. Here, we demonstrated that TGF-β1 significantly upregulated SphK1 expression and S1P production by promoting the phosphorylation of Smad2/3 in PASMC. Further study indicated that SphK1/S1P pathway mediated TGF-β1-induced Notch3 activation in PASMC. In addition, we showed that TGF-β1 significantly induced proliferation of PASMC, while pre-inhibition of Smad2/3 phosphorylation with SB431542 or silencing SphK1 using small interfering RNA in advance, or pre-blocking Notch3 pathway with N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), attenuated TGF-β1-induced PASMC proliferation. Taken together, our study indicates that Smad2/3/SphK1/S1P/Notch3 pathway mediates TGF-β1-induced PASMC proliferation and suggests this pathway as a potential therapeutic target in the prevention and treatment of pulmonary hypertension.https://doi.org/10.1177/2045894018816977 |
| spellingShingle | Jian Wang Wei Feng Fangwei Li Wenhua Shi Cui Zhai Shaojun Li Yanting Zhu Xin Yan Qingting Wang Lu Liu Xinming Xie Manxiang Li SphK1/S1P mediates TGF-β1-induced proliferation of pulmonary artery smooth muscle cells and its potential mechanisms Pulmonary Circulation |
| title | SphK1/S1P mediates TGF-β1-induced proliferation of pulmonary artery smooth muscle cells and its potential mechanisms |
| title_full | SphK1/S1P mediates TGF-β1-induced proliferation of pulmonary artery smooth muscle cells and its potential mechanisms |
| title_fullStr | SphK1/S1P mediates TGF-β1-induced proliferation of pulmonary artery smooth muscle cells and its potential mechanisms |
| title_full_unstemmed | SphK1/S1P mediates TGF-β1-induced proliferation of pulmonary artery smooth muscle cells and its potential mechanisms |
| title_short | SphK1/S1P mediates TGF-β1-induced proliferation of pulmonary artery smooth muscle cells and its potential mechanisms |
| title_sort | sphk1 s1p mediates tgf β1 induced proliferation of pulmonary artery smooth muscle cells and its potential mechanisms |
| url | https://doi.org/10.1177/2045894018816977 |
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