Atheroprotective effects of methotrexate via the inhibition of YAP/TAZ under disturbed flow
Abstract Background Atherosclerosis preferentially develops in regions of disturbed flow (DF). Emerging evidence indicates that yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), which are both effectors of the Hippo pathway, sense different blood flow patter...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-11-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12967-019-02135-8 |
| _version_ | 1819208941036371968 |
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| author | Dandan Liu Hang Lv Qi Liu Yanli Sun Shenglong Hou Lu Zhang Mengyue Yang Baihe Han Gang wang Xuedong Wang Wenjuan Du Honggang Nie Ruoxi Zhang Xingtao Huang Jingbo Hou Bo Yu |
| author_facet | Dandan Liu Hang Lv Qi Liu Yanli Sun Shenglong Hou Lu Zhang Mengyue Yang Baihe Han Gang wang Xuedong Wang Wenjuan Du Honggang Nie Ruoxi Zhang Xingtao Huang Jingbo Hou Bo Yu |
| author_sort | Dandan Liu |
| collection | DOAJ |
| description | Abstract Background Atherosclerosis preferentially develops in regions of disturbed flow (DF). Emerging evidence indicates that yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), which are both effectors of the Hippo pathway, sense different blood flow patterns and regulate atherosclerotic lesions. We previously found that methotrexate (MTX) reduces in-stent neoatherosclerosis, decreases the plaque burden, and has an effect on local fluid shear stress. Here, we investigated the atheroprotective effect of MTX under DF and the mechanisms underlying these properties. Methods Human umbilical vein endothelial cells (HUVECs) were subjected to biomechanical stretch using a parallel-plate flow system and treated with or without MTX at therapeutically relevant concentrations. Additionally, an extravascular device was used to induce DF in the left common carotid artery of C57BL/6 mice, followed by treatment with MTX or 0.9% saline. The artery was then assessed histopathologically after 4 weeks on a Western diet. Results We observed that MTX significantly inhibited DF-induced endothelial YAP/TAZ activation. Furthermore, it markedly decreased pro-inflammatory factor secretion and monocyte adhesion in HUVECs but had no effect on apoptosis. Mechanistically, AMPKa1 depletion attenuated these effects of MTX. Accordingly, MTX decreased DF-induced plaque formation, which was accompanied by YAP/TAZ downregulation in vivo. Conclusions Taken together, we conclude that MTX exerts protective effects via the AMP-dependent kinase (AMPK)-YAP/TAZ pathway. These results provide a basis for the prevention and treatment of atherosclerosis via the inhibition of YAP/TAZ. |
| first_indexed | 2024-12-23T05:47:23Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-12-23T05:47:23Z |
| publishDate | 2019-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-99a0b1353290425bb0ca94f901f609b42022-12-21T17:58:03ZengBMCJournal of Translational Medicine1479-58762019-11-0117111210.1186/s12967-019-02135-8Atheroprotective effects of methotrexate via the inhibition of YAP/TAZ under disturbed flowDandan Liu0Hang Lv1Qi Liu2Yanli Sun3Shenglong Hou4Lu Zhang5Mengyue Yang6Baihe Han7Gang wang8Xuedong Wang9Wenjuan Du10Honggang Nie11Ruoxi Zhang12Xingtao Huang13Jingbo Hou14Bo Yu15Division Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical UniversityKey Laboratories of the Education Ministry for Myocardial Ischemia Mechanisms and TreatmentDivision Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical UniversityDivision Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical UniversityDivision Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical UniversityDivision Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical UniversityDivision Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical UniversityDivision Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical UniversityDivision Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical UniversityDivision Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical UniversityDivision Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical UniversityDivision Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical UniversityDivision Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical UniversityDivision Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical UniversityDivision Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical UniversityDivision Department of Cardiology Organization, The Second Affiliated Hospital of Harbin Medical UniversityAbstract Background Atherosclerosis preferentially develops in regions of disturbed flow (DF). Emerging evidence indicates that yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), which are both effectors of the Hippo pathway, sense different blood flow patterns and regulate atherosclerotic lesions. We previously found that methotrexate (MTX) reduces in-stent neoatherosclerosis, decreases the plaque burden, and has an effect on local fluid shear stress. Here, we investigated the atheroprotective effect of MTX under DF and the mechanisms underlying these properties. Methods Human umbilical vein endothelial cells (HUVECs) were subjected to biomechanical stretch using a parallel-plate flow system and treated with or without MTX at therapeutically relevant concentrations. Additionally, an extravascular device was used to induce DF in the left common carotid artery of C57BL/6 mice, followed by treatment with MTX or 0.9% saline. The artery was then assessed histopathologically after 4 weeks on a Western diet. Results We observed that MTX significantly inhibited DF-induced endothelial YAP/TAZ activation. Furthermore, it markedly decreased pro-inflammatory factor secretion and monocyte adhesion in HUVECs but had no effect on apoptosis. Mechanistically, AMPKa1 depletion attenuated these effects of MTX. Accordingly, MTX decreased DF-induced plaque formation, which was accompanied by YAP/TAZ downregulation in vivo. Conclusions Taken together, we conclude that MTX exerts protective effects via the AMP-dependent kinase (AMPK)-YAP/TAZ pathway. These results provide a basis for the prevention and treatment of atherosclerosis via the inhibition of YAP/TAZ.http://link.springer.com/article/10.1186/s12967-019-02135-8MethotrexateHuman umbilical vein endothelial cellsYAP/TAZShear stressAMP-dependent kinase |
| spellingShingle | Dandan Liu Hang Lv Qi Liu Yanli Sun Shenglong Hou Lu Zhang Mengyue Yang Baihe Han Gang wang Xuedong Wang Wenjuan Du Honggang Nie Ruoxi Zhang Xingtao Huang Jingbo Hou Bo Yu Atheroprotective effects of methotrexate via the inhibition of YAP/TAZ under disturbed flow Journal of Translational Medicine Methotrexate Human umbilical vein endothelial cells YAP/TAZ Shear stress AMP-dependent kinase |
| title | Atheroprotective effects of methotrexate via the inhibition of YAP/TAZ under disturbed flow |
| title_full | Atheroprotective effects of methotrexate via the inhibition of YAP/TAZ under disturbed flow |
| title_fullStr | Atheroprotective effects of methotrexate via the inhibition of YAP/TAZ under disturbed flow |
| title_full_unstemmed | Atheroprotective effects of methotrexate via the inhibition of YAP/TAZ under disturbed flow |
| title_short | Atheroprotective effects of methotrexate via the inhibition of YAP/TAZ under disturbed flow |
| title_sort | atheroprotective effects of methotrexate via the inhibition of yap taz under disturbed flow |
| topic | Methotrexate Human umbilical vein endothelial cells YAP/TAZ Shear stress AMP-dependent kinase |
| url | http://link.springer.com/article/10.1186/s12967-019-02135-8 |
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