Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis

被引：92

作者：

Flach, Rachel J. Roth ^{[1
]}

Skoura, Athanasia ^{[2
]}

Matevossian, Anouch ^{[1
]}

Danai, Laura V. ^{[1
]}

Zheng, Wei ^{[2
]}

Cortes, Christian ^{[2
]}

Bhattacharya, Samit K. ^{[3
]}

Aouadi, Myriam ^{[1
]}

Hagan, Nana ^{[1
]}

Yawe, Joseph C. ^{[1
]}

Vangala, Pranitha ^{[1
]}

Menendez, Lorena Garcia ^{[1
]}

Cooper, Marcus P. ^{[4
]}

Fitzgibbons, Timothy P. ^{[4
]}

Buckbinder, Leonard ^{[2
]}

Czech, Michael P. ^{[1
]}

机构：

[1] Univ Massachusetts, Med Ctr, Program Mol Med, Worcester, MA 01605 USA

[2] Cardiovasc & Metab Res Unit, Cambridge, MA 02139 USA

[3] Worldwide Med Chem Pfizer, Cambridge, MA 02139 USA

[4] Univ Massachusetts, Sch Med, Div Cardiovasc Med, Worcester, MA 01605 USA

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

关键词：

NF-KAPPA-B; P-SELECTIN; MICE; ACTIVATION; EXPRESSION; ICAM-1; INHIBITION; PATHWAY; VCAM-1; CELLS;

D O I：

10.1038/ncomms9995

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 NFkB, 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.

引用

页数：11

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