Tumor Necrosis Factor Receptor-Associated Factor 1 (TRAF1) Deficiency Attenuates Atherosclerosis in Mice by Impairing Monocyte Recruitment to the Vessel Wall

Article

关键词: NF-KAPPA-B;    IN-VIVO;    GENE-EXPRESSION;    CD40 LIGAND;    CELLS;    ACTIVATION;    INFLAMMATION;    INHIBITION;    INDUCTION;    REGULATOR;   

DOI  :  10.1161/CIRCULATIONAHA.109.895037

来源: SCIE

【 摘 要 】

Background-Members of the tumor necrosis factor superfamily, such as tumor necrosis factor-alpha, potently promote atherogenesis in mice and humans. Tumor necrosis factor receptor-associated factors (TRAFs) are cytoplasmic adaptor proteins for this group of cytokines. Methods and Results-This study tested the hypothesis that TRAF1 modulates atherogenesis in vivo. TRAF1(-/-)/ LDLR(-/-) mice that consumed a high-cholesterol diet for 18 weeks developed significantly smaller atherosclerotic lesions than LDLR(-/-) (LDL receptor-deficient) control animals. As the most prominent change in histological composition, plaques of TRAF1-deficient animals contained significantly fewer macrophages. Bone marrow transplantations revealed that TRAF1 deficiency in both hematopoietic and vascular resident cells contributed to the reduction in atherogenesis observed. Mechanistic studies showed that deficiency of TRAF1 in endothelial cells and monocytes reduced adhesion of inflammatory cells to the endothelium in static and dynamic assays. Impaired adhesion coincided with reduced cell spreading, actin polymerization, and CD29 expression in macrophages, as well as decreased expression of the adhesion molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in endothelial cells. Small interfering RNA studies in human cells verified these findings. Furthermore, TRAF1 messenger RNA levels were significantly elevated in the blood of patients with acute coronary syndrome. Conclusions-TRAF1 deficiency attenuates atherogenesis in mice, most likely owing to impaired monocyte recruitment to the vessel wall. These data identify TRAF1 as a potential treatment target for atherosclerosis. (Circulation. 2010;121:2033-2044.)

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