Inhibition of Sphingosine-1-Phosphate Receptor 2 Prevents Thoracic Aortic Dissection and Rupture
Background: Numerous pieces of evidence have indicated that thoracic aortic dissection (TAD) is an inflammatory disease. Sphingosine-1-phosphate receptor 2 (S1PR2) signaling is a driver in multiple inflammatory diseases. Here, we examined the S1PR2 expression in TAD lesions and explored the effect o...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2021-12-01
|
| Series: | Frontiers in Cardiovascular Medicine |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2021.748486/full |
| _version_ | 1819004726708011008 |
|---|---|
| author | Guangwei Pan Guangwei Pan Guangwei Pan Mengyang Liao Mengyang Liao Mengyang Liao Yong Dai Yong Dai Yong Dai Yang Li Xiaole Yan Xiaole Yan Xiaole Yan Wuqian Mai Wuqian Mai Wuqian Mai Jinping Liu Yuhua Liao Yuhua Liao Yuhua Liao Zhihua Qiu Zhihua Qiu Zhihua Qiu Zihua Zhou Zihua Zhou Zihua Zhou |
| author_facet | Guangwei Pan Guangwei Pan Guangwei Pan Mengyang Liao Mengyang Liao Mengyang Liao Yong Dai Yong Dai Yong Dai Yang Li Xiaole Yan Xiaole Yan Xiaole Yan Wuqian Mai Wuqian Mai Wuqian Mai Jinping Liu Yuhua Liao Yuhua Liao Yuhua Liao Zhihua Qiu Zhihua Qiu Zhihua Qiu Zihua Zhou Zihua Zhou Zihua Zhou |
| author_sort | Guangwei Pan |
| collection | DOAJ |
| description | Background: Numerous pieces of evidence have indicated that thoracic aortic dissection (TAD) is an inflammatory disease. Sphingosine-1-phosphate receptor 2 (S1PR2) signaling is a driver in multiple inflammatory diseases. Here, we examined the S1PR2 expression in TAD lesions and explored the effect of interfering with S1PR2 on TAD formation and progression.Methods: Aorta specimens and blood samples were collected from patients with TAD and matched controls. The expression of S1PR1, S1PR2, and S1PR3 was examined. The effect of inhibiting S1PR2 on TAD was evaluated in a TAD mouse model induced by β-aminopropionitrile fumarate (BAPN) and AngII. The presence of sphingosine kinase 1 (SPHK1), S1P, and neutrophil extracellular traps (NETs) was investigated. Further, the possible association between S1PR2 signaling and NETs in TAD was analyzed.Results: In the aortic tissues of patients with TAD and a mouse model, the S1PR2 expression was significantly up-regulated. In the TAD mouse model, JTE013, a specific S1PR2 antagonist, not only blunted the TAD formation and aortic rupture, but also preserved the elastic fiber architecture, reduced the smooth muscle cells apoptosis level, and mitigated the aortic wall inflammation. Augmented tissue protein expression of SPHK1, citrullinated histone H3 (CitH3, a specific marker of NETs), and serum S1P, CitH3 were detected in TAD patients. Surgical repair normalized the serum S1P and CitH3 levels. Immunofluorescence staining revealed that S1PR2 colocalized with NETs. The protein expression levels of SPHK1 and serum S1P levels positively correlated with the protein expression and serum levels of CitH3, separately. Furthermore, JTE013 treatment reduced NETs accumulation.Conclusion: Inhibiting S1PR2 attenuates TAD formation and prevents aortic rupture. Targeting S1PR2 may provide a promising treatment strategy against TAD. |
| first_indexed | 2024-12-20T23:41:29Z |
| format | Article |
| id | doaj.art-e7f555ddca3b424d8b65ca45b4270a9c |
| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-12-20T23:41:29Z |
| publishDate | 2021-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-e7f555ddca3b424d8b65ca45b4270a9c2022-12-21T19:23:05ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2021-12-01810.3389/fcvm.2021.748486748486Inhibition of Sphingosine-1-Phosphate Receptor 2 Prevents Thoracic Aortic Dissection and RuptureGuangwei Pan0Guangwei Pan1Guangwei Pan2Mengyang Liao3Mengyang Liao4Mengyang Liao5Yong Dai6Yong Dai7Yong Dai8Yang Li9Xiaole Yan10Xiaole Yan11Xiaole Yan12Wuqian Mai13Wuqian Mai14Wuqian Mai15Jinping Liu16Yuhua Liao17Yuhua Liao18Yuhua Liao19Zhihua Qiu20Zhihua Qiu21Zhihua Qiu22Zihua Zhou23Zihua Zhou24Zihua Zhou25Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaKey Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaKey Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaKey Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaKey Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaKey Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaKey Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaKey Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaKey Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaBackground: Numerous pieces of evidence have indicated that thoracic aortic dissection (TAD) is an inflammatory disease. Sphingosine-1-phosphate receptor 2 (S1PR2) signaling is a driver in multiple inflammatory diseases. Here, we examined the S1PR2 expression in TAD lesions and explored the effect of interfering with S1PR2 on TAD formation and progression.Methods: Aorta specimens and blood samples were collected from patients with TAD and matched controls. The expression of S1PR1, S1PR2, and S1PR3 was examined. The effect of inhibiting S1PR2 on TAD was evaluated in a TAD mouse model induced by β-aminopropionitrile fumarate (BAPN) and AngII. The presence of sphingosine kinase 1 (SPHK1), S1P, and neutrophil extracellular traps (NETs) was investigated. Further, the possible association between S1PR2 signaling and NETs in TAD was analyzed.Results: In the aortic tissues of patients with TAD and a mouse model, the S1PR2 expression was significantly up-regulated. In the TAD mouse model, JTE013, a specific S1PR2 antagonist, not only blunted the TAD formation and aortic rupture, but also preserved the elastic fiber architecture, reduced the smooth muscle cells apoptosis level, and mitigated the aortic wall inflammation. Augmented tissue protein expression of SPHK1, citrullinated histone H3 (CitH3, a specific marker of NETs), and serum S1P, CitH3 were detected in TAD patients. Surgical repair normalized the serum S1P and CitH3 levels. Immunofluorescence staining revealed that S1PR2 colocalized with NETs. The protein expression levels of SPHK1 and serum S1P levels positively correlated with the protein expression and serum levels of CitH3, separately. Furthermore, JTE013 treatment reduced NETs accumulation.Conclusion: Inhibiting S1PR2 attenuates TAD formation and prevents aortic rupture. Targeting S1PR2 may provide a promising treatment strategy against TAD.https://www.frontiersin.org/articles/10.3389/fcvm.2021.748486/fullthoracic aortic dissectionS1PR2 inhibitionJTE013inflammationneutrophil extracellular traps |
| spellingShingle | Guangwei Pan Guangwei Pan Guangwei Pan Mengyang Liao Mengyang Liao Mengyang Liao Yong Dai Yong Dai Yong Dai Yang Li Xiaole Yan Xiaole Yan Xiaole Yan Wuqian Mai Wuqian Mai Wuqian Mai Jinping Liu Yuhua Liao Yuhua Liao Yuhua Liao Zhihua Qiu Zhihua Qiu Zhihua Qiu Zihua Zhou Zihua Zhou Zihua Zhou Inhibition of Sphingosine-1-Phosphate Receptor 2 Prevents Thoracic Aortic Dissection and Rupture Frontiers in Cardiovascular Medicine thoracic aortic dissection S1PR2 inhibition JTE013 inflammation neutrophil extracellular traps |
| title | Inhibition of Sphingosine-1-Phosphate Receptor 2 Prevents Thoracic Aortic Dissection and Rupture |
| title_full | Inhibition of Sphingosine-1-Phosphate Receptor 2 Prevents Thoracic Aortic Dissection and Rupture |
| title_fullStr | Inhibition of Sphingosine-1-Phosphate Receptor 2 Prevents Thoracic Aortic Dissection and Rupture |
| title_full_unstemmed | Inhibition of Sphingosine-1-Phosphate Receptor 2 Prevents Thoracic Aortic Dissection and Rupture |
| title_short | Inhibition of Sphingosine-1-Phosphate Receptor 2 Prevents Thoracic Aortic Dissection and Rupture |
| title_sort | inhibition of sphingosine 1 phosphate receptor 2 prevents thoracic aortic dissection and rupture |
| topic | thoracic aortic dissection S1PR2 inhibition JTE013 inflammation neutrophil extracellular traps |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2021.748486/full |
| work_keys_str_mv | AT guangweipan inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture AT guangweipan inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture AT guangweipan inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture AT mengyangliao inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture AT mengyangliao inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture AT mengyangliao inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture AT yongdai inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture AT yongdai inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture AT yongdai inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture AT yangli inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture AT xiaoleyan inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture AT xiaoleyan inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture AT xiaoleyan inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture AT wuqianmai inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture AT wuqianmai inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture AT wuqianmai inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture AT jinpingliu inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture AT yuhualiao inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture AT yuhualiao inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture AT yuhualiao inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture AT zhihuaqiu inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture AT zhihuaqiu inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture AT zhihuaqiu inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture AT zihuazhou inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture AT zihuazhou inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture AT zihuazhou inhibitionofsphingosine1phosphatereceptor2preventsthoracicaorticdissectionandrupture |