Sphingosine Kinase 1 Deficiency in Smooth Muscle Cells Protects against Hypoxia-Mediated Pulmonary Hypertension via YAP1 Signaling
Abstract
:1. Introduction
2. Results
2.1. SPHK1 Is Upregulated in the PASMCs of Rodent Models of PH
2.2. Smooth Muscle Cell-Specific Sphk1 Knockout Mice Are Protected from Hypoxia-Induced PH
2.3. Smooth Muscle Cell-Specific Sphk1 Knockout Mice Are Protected from Hypoxia Plus Sugen-Mediated Pulmonary Hypertension
2.4. PASMCs Isolated from Sphk1-/- Mice Are Less Proliferative and Less Viable
2.5. Hypoxia Induces YAP1 and TAZ Expression in the Lungs of Rodent Models of PH
2.6. Hypoxia and S1P Stimulate YAP1 Nuclear Translocation in PASMCs
2.7. S1P Promotes YAP1 Nuclear Translocation via Ligation to S1PR2
2.8. YAP1 Regulates S1P-Mediated Proliferation in hPASMCs
2.9. YAP1 Inhibition with Verteporfin Prevents Hypoxia-Mediated PH and Pulmonary Vascular Remodeling in Mice
2.10. YAP1 Inhibition with Verteporfin Attenuates Hypoxia/Sugen-Mediated PH and Pulmonary Vascular Remodeling in Rats
3. Discussion
4. Materials and Methods
4.1. Reagents, Drugs, and Antibodies
4.2. Mouse PASMC Isolation
4.3. Cell Proliferation, Viability, Apoptosis, and Lactate Dehydrogenase Assays
4.4. Lung Tissue Immunofluorescence Staining
4.5. Adenoviral Constructs of Wild-Type and Dominant-Negative SPHK1 Plasmids
4.6. Transfection of Plasmid DNA and Small Interfering RNA in hPASMCs
4.7. Animal Models of Pulmonary Hypertension and Hemodynamic Measurements
4.8. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Chen, J.; Lockett, A.; Zhao, S.; Huang, L.S.; Wang, Y.; Wu, W.; Tang, M.; Haider, S.; Velez Rendon, D.; Khan, R.; et al. Sphingosine Kinase 1 Deficiency in Smooth Muscle Cells Protects against Hypoxia-Mediated Pulmonary Hypertension via YAP1 Signaling. Int. J. Mol. Sci. 2022, 23, 14516. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314516
Chen J, Lockett A, Zhao S, Huang LS, Wang Y, Wu W, Tang M, Haider S, Velez Rendon D, Khan R, et al. Sphingosine Kinase 1 Deficiency in Smooth Muscle Cells Protects against Hypoxia-Mediated Pulmonary Hypertension via YAP1 Signaling. International Journal of Molecular Sciences. 2022; 23(23):14516. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314516
Chicago/Turabian StyleChen, Jiwang, Angelia Lockett, Shuangping Zhao, Long Shuang Huang, Yifan Wang, Weiwen Wu, Ming Tang, Shahzaib Haider, Daniela Velez Rendon, Raheel Khan, and et al. 2022. "Sphingosine Kinase 1 Deficiency in Smooth Muscle Cells Protects against Hypoxia-Mediated Pulmonary Hypertension via YAP1 Signaling" International Journal of Molecular Sciences 23, no. 23: 14516. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314516