Sphingosine Kinase 1 Deficiency in Smooth Muscle Cells Protects against Hypoxia-Mediated Pulmonary Hypertension via YAP1 Signaling
Sphingosine kinase 1 (SPHK1) and the sphingosine-1-phosphate (S1P) signaling pathway have been shown to play a role in pulmonary arterial hypertension (PAH). S1P is an important stimulus for pulmonary artery smooth muscle cell (PASMC) proliferation and pulmonary vascular remodeling. We aimed to exam...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/23/14516 |
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| author | Jiwang Chen Angelia Lockett Shuangping Zhao Long Shuang Huang Yifan Wang Weiwen Wu Ming Tang Shahzaib Haider Daniela Velez Rendon Raheel Khan Bing Liu Nicholas Felesena Justin R. Sysol Daniela Valdez-Jasso Haiyang Tang Yang Bai Viswanathan Natarajan Roberto F. Machado |
| author_facet | Jiwang Chen Angelia Lockett Shuangping Zhao Long Shuang Huang Yifan Wang Weiwen Wu Ming Tang Shahzaib Haider Daniela Velez Rendon Raheel Khan Bing Liu Nicholas Felesena Justin R. Sysol Daniela Valdez-Jasso Haiyang Tang Yang Bai Viswanathan Natarajan Roberto F. Machado |
| author_sort | Jiwang Chen |
| collection | DOAJ |
| description | Sphingosine kinase 1 (SPHK1) and the sphingosine-1-phosphate (S1P) signaling pathway have been shown to play a role in pulmonary arterial hypertension (PAH). S1P is an important stimulus for pulmonary artery smooth muscle cell (PASMC) proliferation and pulmonary vascular remodeling. We aimed to examine the specific roles of SPHK1 in PASMCs during pulmonary hypertension (PH) progression. We generated smooth muscle cell-specific, <i>Sphk1</i>-deficient (<i>Sphk1<sup>f/f</sup> TaglnCre<sup>+</sup></i>) mice and isolated <i>Sphk1</i>-deficient PASMCs from <i>SPHK1</i> knockout mice. We demonstrated that <i>Sphk1<sup>f/f</sup> TaglnCre<sup>+</sup></i> mice are protected from hypoxia or hypoxia/Sugen-mediated PH, and pulmonary vascular remodeling and that <i>Sphk1</i>-deficient PASMCs are less proliferative compared with ones isolated from wild-type (WT) siblings. S1P or hypoxia activated yes-associated protein 1 (YAP1) signaling by enhancing its translocation to the nucleus, which was dependent on SPHK1 enzymatic activity. Further, verteporfin, a pharmacologic YAP1 inhibitor, attenuated the S1P-mediated proliferation of hPASMCs, hypoxia-mediated PH, and pulmonary vascular remodeling in mice and hypoxia/Sugen-mediated severe PH in rats. Smooth muscle cell-specific SPHK1 plays an essential role in PH via YAP1 signaling, and YAP1 inhibition may have therapeutic potential in treating PH. |
| first_indexed | 2024-03-09T17:47:48Z |
| format | Article |
| id | doaj.art-c3880120feaa46878a9dffa6844bde9f |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T17:47:48Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-c3880120feaa46878a9dffa6844bde9f2023-11-24T11:03:26ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123231451610.3390/ijms232314516Sphingosine Kinase 1 Deficiency in Smooth Muscle Cells Protects against Hypoxia-Mediated Pulmonary Hypertension via YAP1 SignalingJiwang Chen0Angelia Lockett1Shuangping Zhao2Long Shuang Huang3Yifan Wang4Weiwen Wu5Ming Tang6Shahzaib Haider7Daniela Velez Rendon8Raheel Khan9Bing Liu10Nicholas Felesena11Justin R. Sysol12Daniela Valdez-Jasso13Haiyang Tang14Yang Bai15Viswanathan Natarajan16Roberto F. Machado17Department of Medicine, Section of Pulmonary, Critical Care Medicine, Sleep and Allergy, University of Illinois at Chicago, Chicago, IL 60612, USADivision of Pulmonary, Critical Care, Sleep, and Occupational Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Medicine, Section of Pulmonary, Critical Care Medicine, Sleep and Allergy, University of Illinois at Chicago, Chicago, IL 60612, USADepartment of Medicine, Section of Pulmonary, Critical Care Medicine, Sleep and Allergy, University of Illinois at Chicago, Chicago, IL 60612, USADepartment of Medicine, Section of Pulmonary, Critical Care Medicine, Sleep and Allergy, University of Illinois at Chicago, Chicago, IL 60612, USADepartment of Medicine, Section of Pulmonary, Critical Care Medicine, Sleep and Allergy, University of Illinois at Chicago, Chicago, IL 60612, USADepartment of Medicine, Section of Pulmonary, Critical Care Medicine, Sleep and Allergy, University of Illinois at Chicago, Chicago, IL 60612, USADepartment of Medicine, Section of Pulmonary, Critical Care Medicine, Sleep and Allergy, University of Illinois at Chicago, Chicago, IL 60612, USADepartment of Bioengineering, University of Illinois at Chicago, Chicago, IL 60612, USADepartment of Medicine, Section of Pulmonary, Critical Care Medicine, Sleep and Allergy, University of Illinois at Chicago, Chicago, IL 60612, USADepartment of Medicine, Section of Pulmonary, Critical Care Medicine, Sleep and Allergy, University of Illinois at Chicago, Chicago, IL 60612, USADepartment of Medicine, Section of Pulmonary, Critical Care Medicine, Sleep and Allergy, University of Illinois at Chicago, Chicago, IL 60612, USADepartment of Medicine, Section of Pulmonary, Critical Care Medicine, Sleep and Allergy, University of Illinois at Chicago, Chicago, IL 60612, USADepartment of Bioengineering, University of Illinois at Chicago, Chicago, IL 60612, USAState Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510030, ChinaDivision of Pulmonary, Critical Care, Sleep, and Occupational Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Medicine, Section of Pulmonary, Critical Care Medicine, Sleep and Allergy, University of Illinois at Chicago, Chicago, IL 60612, USADivision of Pulmonary, Critical Care, Sleep, and Occupational Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USASphingosine kinase 1 (SPHK1) and the sphingosine-1-phosphate (S1P) signaling pathway have been shown to play a role in pulmonary arterial hypertension (PAH). S1P is an important stimulus for pulmonary artery smooth muscle cell (PASMC) proliferation and pulmonary vascular remodeling. We aimed to examine the specific roles of SPHK1 in PASMCs during pulmonary hypertension (PH) progression. We generated smooth muscle cell-specific, <i>Sphk1</i>-deficient (<i>Sphk1<sup>f/f</sup> TaglnCre<sup>+</sup></i>) mice and isolated <i>Sphk1</i>-deficient PASMCs from <i>SPHK1</i> knockout mice. We demonstrated that <i>Sphk1<sup>f/f</sup> TaglnCre<sup>+</sup></i> mice are protected from hypoxia or hypoxia/Sugen-mediated PH, and pulmonary vascular remodeling and that <i>Sphk1</i>-deficient PASMCs are less proliferative compared with ones isolated from wild-type (WT) siblings. S1P or hypoxia activated yes-associated protein 1 (YAP1) signaling by enhancing its translocation to the nucleus, which was dependent on SPHK1 enzymatic activity. Further, verteporfin, a pharmacologic YAP1 inhibitor, attenuated the S1P-mediated proliferation of hPASMCs, hypoxia-mediated PH, and pulmonary vascular remodeling in mice and hypoxia/Sugen-mediated severe PH in rats. Smooth muscle cell-specific SPHK1 plays an essential role in PH via YAP1 signaling, and YAP1 inhibition may have therapeutic potential in treating PH.https://www.mdpi.com/1422-0067/23/23/14516sphingosine kinase 1S1Ppulmonary artery smooth muscle cellproliferationYAP1verteporfin |
| spellingShingle | Jiwang Chen Angelia Lockett Shuangping Zhao Long Shuang Huang Yifan Wang Weiwen Wu Ming Tang Shahzaib Haider Daniela Velez Rendon Raheel Khan Bing Liu Nicholas Felesena Justin R. Sysol Daniela Valdez-Jasso Haiyang Tang Yang Bai Viswanathan Natarajan Roberto F. Machado Sphingosine Kinase 1 Deficiency in Smooth Muscle Cells Protects against Hypoxia-Mediated Pulmonary Hypertension via YAP1 Signaling International Journal of Molecular Sciences sphingosine kinase 1 S1P pulmonary artery smooth muscle cell proliferation YAP1 verteporfin |
| title | Sphingosine Kinase 1 Deficiency in Smooth Muscle Cells Protects against Hypoxia-Mediated Pulmonary Hypertension via YAP1 Signaling |
| title_full | Sphingosine Kinase 1 Deficiency in Smooth Muscle Cells Protects against Hypoxia-Mediated Pulmonary Hypertension via YAP1 Signaling |
| title_fullStr | Sphingosine Kinase 1 Deficiency in Smooth Muscle Cells Protects against Hypoxia-Mediated Pulmonary Hypertension via YAP1 Signaling |
| title_full_unstemmed | Sphingosine Kinase 1 Deficiency in Smooth Muscle Cells Protects against Hypoxia-Mediated Pulmonary Hypertension via YAP1 Signaling |
| title_short | Sphingosine Kinase 1 Deficiency in Smooth Muscle Cells Protects against Hypoxia-Mediated Pulmonary Hypertension via YAP1 Signaling |
| title_sort | sphingosine kinase 1 deficiency in smooth muscle cells protects against hypoxia mediated pulmonary hypertension via yap1 signaling |
| topic | sphingosine kinase 1 S1P pulmonary artery smooth muscle cell proliferation YAP1 verteporfin |
| url | https://www.mdpi.com/1422-0067/23/23/14516 |
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