Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis

Rachel J. Roth Flach, Athanasia Skoura, Anouch Matevossian, Laura V. Danai, Wei Zheng, Christian Cortes, Samit K. Bhattacharya, Myriam Aouadi, Nana Hagan, Joseph C. Yawe, Pranitha Vangala, Lorena Garcia Menendez, Marcus P. Cooper, Timothy P. Fitzgibbons, Leonard Buckbinder and Michael P. Czech ()
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Rachel J. Roth Flach: Program in Molecular Medicine
Athanasia Skoura: Cardiovascular and Metabolic Research Unit
Anouch Matevossian: Program in Molecular Medicine
Laura V. Danai: Program in Molecular Medicine
Wei Zheng: Cardiovascular and Metabolic Research Unit
Christian Cortes: Cardiovascular and Metabolic Research Unit
Samit K. Bhattacharya: Worldwide Medicinal Chemistry Pfizer
Myriam Aouadi: Program in Molecular Medicine
Nana Hagan: Program in Molecular Medicine
Joseph C. Yawe: Program in Molecular Medicine
Pranitha Vangala: Program in Molecular Medicine
Lorena Garcia Menendez: Program in Molecular Medicine
Marcus P. Cooper: University of Massachusetts Medical School
Timothy P. Fitzgibbons: University of Massachusetts Medical School
Leonard Buckbinder: Cardiovascular and Metabolic Research Unit
Michael P. Czech: Program in Molecular Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: 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−/− mice, we show that MAP4K4 in ECs markedly promotes Western diet-induced aortic macrophage accumulation and atherosclerotic plaque development. Treatment of Apoe−/− and Ldlr−/− 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.

Date: 2015
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DOI: 10.1038/ncomms9995

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