title: AGGF1 is a novel anti-inflammatory factor associated with TNF-α-induced endothelial activation.
abstract: Endothelial activation contributes to the development of vascular inflammation and subsequent vascular diseases, particularly atherosclerosis. AGGF1, a new member of angiogenic factors with a FHA and a G-patch domain, has been shown critical for the regulation of vascular differentiation and angiogenesis. In this study, we found that various inflammatory cytokines strongly induced the expression of AGGF1 in endothelial cells (ECs) and identified AGGF1 as a novel anti-inflammatory factor both in vivo and in vitro. Overexpression of AGGF1 significantly repressed the expression of pro-inflammatory molecules such as E-Selectin, ICAM-1, and IL-8 and the adhesion of monocytes onto ECs activated by TNF-α. Conversely, the knockdown of AGGF1 resulted in the increased expressions of these pro-inflammatory molecules and the enhanced monocyte-EC interaction. We further demonstrated that AGGF1 potently attenuated TNF-α triggered NF-κB pathway, as indicated by the decreased promoter activity, nuclear distribution and phosphorylation of NF-κB p65 subunit as well as the increased protein level of IκBα. This inhibitory effect of AGGF1 was further proved through blocking the phosphorylation of ERK induced by TNF-α. Finally, we showed that the FHA domain of AGGF1 was required for its anti-inflammatory effect. Thus, our findings for the first time demonstrate that AGGF1 suppresses endothelial activation responses to TNF-α by antagonizing the ERK/NF-κB pathway, which makes AGGF1 a promising therapeutic candidate for the prevention and treatment of inflammatory diseases.
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, 5 Yihe Yuan Rd, Beijing 100871, China.
authors.forename: Fang-Yuan
authors.initials: FY
authors.lastname: Hu
authors.forename: Chong
authors.initials: C
authors.lastname: Wu
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Wang
authors.forename: Huiqing
authors.initials: H
authors.lastname: Cao
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Tian
mesh_terms: D042501:Angiogenic Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002448:Cell Adhesion; D002460:Cell Line; D019040:E-Selectin / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: C482200:AGGF1 protein, human; D042501:Angiogenic Proteins; D019040:E-Selectin; D016209:Interleukin-8; D016328:NF-kappa B; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3