title: Transcription factor MEF2C suppresses endothelial cell inflammation via regulation of NF-κB and KLF2.
abstract: Endothelial cells play a major role in the initiation and perpetuation of the inflammatory process in health and disease, including their pivotal role in leukocyte recruitment. The role of pro-inflammatory transcription factors in this process has been well-described, including NF-κB. However, much less is known regarding transcription factors that play an anti-inflammatory role in endothelial cells. Myocyte enhancer factor 2 C (MEF2C) is a transcription factor known to regulate angiogenesis in endothelial cells. Here, we report that MEF2C plays a critical function as an inhibitor of endothelial cell inflammation. Tumor necrosis factor (TNF)-α inhibited MEF2C expression in endothelial cells. Knockdown of MEF2C in endothelial cells resulted in the upregulation of pro-inflammatory molecules and stimulated leukocyte adhesion to endothelial cells. MEF2C knockdown also resulted in NF-κB activation in endothelial cells. Conversely, MEF2C overexpression by adenovirus significantly repressed TNF-α induction of pro-inflammatory molecules, activation of NF-κB, and leukocyte adhesion to endothelial cells. This inhibition of leukocyte adhesion by MEF2C was partially mediated by induction of KLF2. In mice, lipopolysaccharide (LPS)-induced leukocyte adhesion to the retinal vasculature was significantly increased by endothelial cell-specific ablation of MEF2C. Taken together, these results demonstrate that MEF2C is a novel negative regulator of inflammation in endothelial cells and may represent a therapeutic target for vascular inflammation.
authors.affiliation: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Xu
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Lijuan
authors.initials: L
authors.lastname: Wu
authors.forename: Debasish
authors.initials: D
authors.lastname: Maiti
authors.forename: Liudmila
authors.initials: L
authors.lastname: Cebotaru
authors.forename: Elia J
authors.initials: EJ
authors.lastname: Duh
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D064326:MEF2 Transcription Factors / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D008070:Lipopolysaccharides; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha