Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis
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Flach-2015-Endothelial Protein.pdf
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Author(s)
Roth Flach, Rachel J.
Skoura, Athanasia
Matevossian, Anouch
Zheng, Wei
Cortes, Christian
Bhattacharya, Samit K.
Aouadi, Myriam
Hagan, Nana
Yawe, Joseph C.
Vangala, Pranitha
Date Issued
December 2015
Journal
Nature Communications
Publisher
Nature Publishing Group
Citation
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.
Version
Final published version
Abstract
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.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1038/ncomms9995
