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.
Highlights
Signalling pathways that control endothelial cell (EC) permeability, leukocyte adhesion and inflammation are pivotal for atherosclerosis initiation and progression
Deletion of Map4k4 in ECs in mice is accompanied by reduced aortic macrophage and chemokine content, reduced EC adhesion molecule expression as well as attenuated leukocyte homing to atherosclerotic plaques
To assess whether Map4k4 expression was altered by atherosclerotic risk factors such as obesity, mice were fed a standard chow or 60% high-fat diet (HFD) for 16 weeks, and several tissues were isolated for quantitative reverse transcription–PCR analysis
Summary
Signalling pathways that control endothelial cell (EC) permeability, leukocyte adhesion and inflammation are pivotal for atherosclerosis initiation and progression. 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. Chronic vascular inflammation can increase VCAM-1 expression in the vessel wall, which has been implicated in atherosclerotic lesion initiation and progression[4,5,6,7,8]. Inhibiting upstream signalling cascades that promote adhesion molecule expression such as nuclear factor kappa light-chain enhancer of activated B cells (NFkB) in ECs ameliorates atherosclerosis progression[16]. Deletion of Map4k4 in ECs in mice is accompanied by reduced aortic macrophage and chemokine content, reduced EC adhesion molecule expression as well as attenuated leukocyte homing to atherosclerotic plaques. The data presented here indicate a central role for MAP4K4 in promoting vascular inflammation and atherosclerosis
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