title: Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis.
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.
authors.affiliation: Program in Molecular Medicine, Worcester, Massachusetts 01605, USA.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Roth Flach
authors.affiliation: Cardiovascular and Metabolic Research Unit, Cambridge, Massachusetts 02139, USA.
authors.forename: Athanasia
authors.initials: A
authors.lastname: Skoura
authors.affiliation: Program in Molecular Medicine, Worcester, Massachusetts 01605, USA.
authors.forename: Anouch
authors.initials: A
authors.lastname: Matevossian
authors.affiliation: Program in Molecular Medicine, Worcester, Massachusetts 01605, USA.
authors.forename: Laura V
authors.initials: LV
authors.lastname: Danai
authors.affiliation: Cardiovascular and Metabolic Research Unit, Cambridge, Massachusetts 02139, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Cardiovascular and Metabolic Research Unit, Cambridge, Massachusetts 02139, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Cortes
authors.affiliation: Worldwide Medicinal Chemistry Pfizer, Cambridge, Massachusetts 02139, USA.
authors.forename: Samit K
authors.initials: SK
authors.lastname: Bhattacharya
authors.affiliation: Program in Molecular Medicine, Worcester, Massachusetts 01605, USA.
authors.forename: Myriam
authors.initials: M
authors.lastname: Aouadi
authors.affiliation: Program in Molecular Medicine, Worcester, Massachusetts 01605, USA.
authors.forename: Nana
authors.initials: N
authors.lastname: Hagan
authors.affiliation: Program in Molecular Medicine, Worcester, Massachusetts 01605, USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Yawe
authors.affiliation: Program in Molecular Medicine, Worcester, Massachusetts 01605, USA.
authors.forename: Pranitha
authors.initials: P
authors.lastname: Vangala
authors.affiliation: Program in Molecular Medicine, Worcester, Massachusetts 01605, USA.
authors.forename: Lorena Garcia
authors.initials: LG
authors.lastname: Menendez
authors.affiliation: Division of Cardiovascular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Marcus P
authors.initials: MP
authors.lastname: Cooper
authors.affiliation: Division of Cardiovascular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Fitzgibbons
authors.affiliation: Cardiovascular and Metabolic Research Unit, Cambridge, Massachusetts 02139, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Buckbinder
authors.affiliation: Program in Molecular Medicine, Worcester, Massachusetts 01605, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Czech
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D014652:Vascular Diseases / Q000235:genetics / Q000378:metabolism*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D000631:Aminopyridines; D001057:Apolipoproteins E; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D011973:Receptors, LDL; D000097782:NF-kappaB-Inducing Kinase; C000607524:PF-6260933