2. Academic Validation
  3. Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis

Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis

  • Nat Commun. 2015 Dec 21;6:8995. doi: 10.1038/ncomms9995.
Rachel J Roth Flach 1,  Athanasia Skoura 2,  Anouch Matevossian 1,  Laura V Danai 1,  Wei Zheng 2,  Christian Cortes 2,  Samit K Bhattacharya 3,  Myriam Aouadi 1,  Nana Hagan 1,  Joseph C Yawe 1,  Pranitha Vangala 1,  Lorena Garcia Menendez 1,  Marcus P Cooper 4,  Timothy P Fitzgibbons 4,  Leonard Buckbinder 2,  Michael P Czech 1
Affiliations

Affiliations

  • 1 Program in Molecular Medicine, Worcester, Massachusetts 01605, USA.
  • 2 Cardiovascular and Metabolic Research Unit, Cambridge, Massachusetts 02139, USA.
  • 3 Worldwide Medicinal Chemistry Pfizer, Cambridge, Massachusetts 02139, USA.
  • 4 Division of Cardiovascular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
PMID: 26688060 DOI: 10.1038/ncomms9995
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.

Figures
Products