Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis
Signalling pathways that control endothelial cell (EC) permeability, leukocyte adhesion and inflammation are pivotal for atherosclerosis initiation and progression. Here we demonstrate that the Sterile-20-like mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), which has been implicate...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Nature Publishing Group
2016
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| Online Access: | http://hdl.handle.net/1721.1/101728 https://orcid.org/0000-0002-8206-8003 |
| _version_ | 1826208242179506176 |
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| author | Roth Flach, Rachel J. Skoura, Athanasia Matevossian, Anouch Zheng, Wei Cortes, Christian Bhattacharya, Samit K. Aouadi, Myriam Hagan, Nana Yawe, Joseph C. Vangala, Pranitha Menendez, Lorena Garcia Cooper, Marcus P. Fitzgibbons, Timothy P. Buckbinder, Leonard Czech, Michael P. Danai, Laura V |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Roth Flach, Rachel J. Skoura, Athanasia Matevossian, Anouch Zheng, Wei Cortes, Christian Bhattacharya, Samit K. Aouadi, Myriam Hagan, Nana Yawe, Joseph C. Vangala, Pranitha Menendez, Lorena Garcia Cooper, Marcus P. Fitzgibbons, Timothy P. Buckbinder, Leonard Czech, Michael P. Danai, Laura V |
| author_sort | Roth Flach, Rachel J. |
| collection | MIT |
| description | Signalling pathways that control endothelial cell (EC) permeability, leukocyte adhesion and inflammation are pivotal for atherosclerosis initiation and progression. Here we demonstrate that the Sterile-20-like mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), which has been implicated in inflammation, is abundantly expressed in ECs and in atherosclerotic plaques from mice and humans. On the basis of endothelial-specific MAP4K4 gene silencing and gene ablation experiments in Apoe[superscript −/−] mice, we show that MAP4K4 in ECs markedly promotes Western diet-induced aortic macrophage accumulation and atherosclerotic plaque development. Treatment of Apoe[superscript −/−] and Ldlr[superscript −/−] mice with a selective small-molecule MAP4K4 inhibitor also markedly reduces atherosclerotic lesion area. MAP4K4 silencing in cultured ECs attenuates cell surface adhesion molecule expression while reducing nuclear localization and activity of NFκB, which is critical for promoting EC activation and atherosclerosis. Taken together, these results reveal that MAP4K4 is a key signalling node that promotes immune cell recruitment in atherosclerosis. |
| first_indexed | 2024-09-23T14:02:45Z |
| format | Article |
| id | mit-1721.1/101728 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T14:02:45Z |
| publishDate | 2016 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1017282022-10-01T18:48:21Z Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis Roth Flach, Rachel J. Skoura, Athanasia Matevossian, Anouch Zheng, Wei Cortes, Christian Bhattacharya, Samit K. Aouadi, Myriam Hagan, Nana Yawe, Joseph C. Vangala, Pranitha Menendez, Lorena Garcia Cooper, Marcus P. Fitzgibbons, Timothy P. Buckbinder, Leonard Czech, Michael P. Danai, Laura V Koch Institute for Integrative Cancer Research at MIT Danai, Laura Signalling pathways that control endothelial cell (EC) permeability, leukocyte adhesion and inflammation are pivotal for atherosclerosis initiation and progression. Here we demonstrate that the Sterile-20-like mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), which has been implicated in inflammation, is abundantly expressed in ECs and in atherosclerotic plaques from mice and humans. On the basis of endothelial-specific MAP4K4 gene silencing and gene ablation experiments in Apoe[superscript −/−] mice, we show that MAP4K4 in ECs markedly promotes Western diet-induced aortic macrophage accumulation and atherosclerotic plaque development. Treatment of Apoe[superscript −/−] and Ldlr[superscript −/−] mice with a selective small-molecule MAP4K4 inhibitor also markedly reduces atherosclerotic lesion area. MAP4K4 silencing in cultured ECs attenuates cell surface adhesion molecule expression while reducing nuclear localization and activity of NFκB, which is critical for promoting EC activation and atherosclerosis. Taken together, these results reveal that MAP4K4 is a key signalling node that promotes immune cell recruitment in atherosclerosis. 2016-03-17T00:13:48Z 2016-03-17T00:13:48Z 2015-12 2015-06 Article http://purl.org/eprint/type/JournalArticle 2041-1723 http://hdl.handle.net/1721.1/101728 Roth Flach, Rachel J., Athanasia Skoura, Anouch Matevossian, Laura V. Danai, Wei Zheng, Christian Cortes, Samit K. Bhattacharya, et al. “Endothelial Protein Kinase MAP4K4 Promotes Vascular Inflammation and Atherosclerosis.” Nat Comms 6 (December 21, 2015): 8995. https://orcid.org/0000-0002-8206-8003 en_US http://dx.doi.org/10.1038/ncomms9995 Nature Communications Creative Commons Attribution http://creativecommons.org/licenses/by/4.0/ application/pdf Nature Publishing Group Nature Publishing Group |
| spellingShingle | Roth Flach, Rachel J. Skoura, Athanasia Matevossian, Anouch Zheng, Wei Cortes, Christian Bhattacharya, Samit K. Aouadi, Myriam Hagan, Nana Yawe, Joseph C. Vangala, Pranitha Menendez, Lorena Garcia Cooper, Marcus P. Fitzgibbons, Timothy P. Buckbinder, Leonard Czech, Michael P. Danai, Laura V Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis |
| title | Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis |
| title_full | Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis |
| title_fullStr | Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis |
| title_full_unstemmed | Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis |
| title_short | Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis |
| title_sort | endothelial protein kinase map4k4 promotes vascular inflammation and atherosclerosis |
| url | http://hdl.handle.net/1721.1/101728 https://orcid.org/0000-0002-8206-8003 |
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