Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis.

Autor:	Roth Flach RJ; Program in Molecular Medicine, Worcester, Massachusetts 01605, USA., Skoura A; Cardiovascular and Metabolic Research Unit, Cambridge, Massachusetts 02139, USA., Matevossian A; Program in Molecular Medicine, Worcester, Massachusetts 01605, USA., Danai LV; Program in Molecular Medicine, Worcester, Massachusetts 01605, USA., Zheng W; Cardiovascular and Metabolic Research Unit, Cambridge, Massachusetts 02139, USA., Cortes C; Cardiovascular and Metabolic Research Unit, Cambridge, Massachusetts 02139, USA., Bhattacharya SK; Worldwide Medicinal Chemistry Pfizer, Cambridge, Massachusetts 02139, USA., Aouadi M; Program in Molecular Medicine, Worcester, Massachusetts 01605, USA., Hagan N; Program in Molecular Medicine, Worcester, Massachusetts 01605, USA., Yawe JC; Program in Molecular Medicine, Worcester, Massachusetts 01605, USA., Vangala P; Program in Molecular Medicine, Worcester, Massachusetts 01605, USA., Menendez LG; Program in Molecular Medicine, Worcester, Massachusetts 01605, USA., Cooper MP; Division of Cardiovascular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA., Fitzgibbons TP; Division of Cardiovascular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA., Buckbinder L; Cardiovascular and Metabolic Research Unit, Cambridge, Massachusetts 02139, USA., Czech MP; Program in Molecular Medicine, Worcester, Massachusetts 01605, USA.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2015 Dec 21; Vol. 6, pp. 8995. Date of Electronic Publication: 2015 Dec 21.
DOI:	10.1038/ncomms9995
Abstrakt:	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.
Databáze:	MEDLINE
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