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Zhenhua Xu, Junsong Gong, Takeshi Yoshida, Lijuan Wu, Liudmila Cebotaru, Elia Duh; Myocyte Enhancer Factor 2C (MEF2C) suppresses inflammation in retinal endothelial cells via regulation of KLF2. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3241.
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Inflammation is important in multiple ocular diseases, including post-surgical macular edema and retinal vasculitis. Endothelial cells play a vital role in the inflammatory process, including interaction with leukocytes. We previously found that the transcription factor MEF2C regulates angiogenesis in endothelial cells. The objective of this study was to determine the role of MEF2C in regulating inflammation in retinal endothelial cells both in vitro and in vivo and to gain insights into the mechanisms of MEF2C action.
Human retinal endothelial cells (HRECs) were treated with TNF-α and the expression of MEF2C was assayed by real-time PCR and Western blot analysis. The functional relevance of MEF2C to inflammation was measured by in vitro leukocyte adhesion assay. Adenovirus-mediated MEF2C overexpression was performed to determine the effect of MEF2C on TNF-α-induced leukocyte adhesion and pro-inflammatory gene expression. Endothelial cell specific mef2c conditional knockout mice were used in a lipopolysaccharide (LPS)-induced acute inflammation mouse model to investigate the role of MEF2C in regulating leukocyte adhesion to retinal vasculature in vivo. siRNA was transfected into HRECs to knockdown the expression of krueppel-like factor 2 (KLF2).
TNF-α inhibited MEF2C expression and activity in retinal endothelial cells. Overexpression of MEF2C in retinal endothelial cells significantly suppressed TNF-α-induced leukocyte adhesion and the expression of multiple pro-inflammatory genes. Leukocyte adhesion to the retinal vasculature was induced in the LPS- injection model in endothelial cell-specific mef2c knockout mice compared to littermate control mice. Overexpression of MEF2C significantly increased KLF2 protein level in endothelial cells. The inhibition of KLF2 by siRNA in endothelial cells attenuated the inhibitory effect of MEF2C on the expression of pro-inflammatory genes and TNF-α-induced leukocyte adhesion to endothelial cells.
These results indicate that MEF2C is a transcription factor that can modulate the inflammatory response in endothelial cells both in vitro and in vivo. KLF2 might be an important mechanism for MEF2C in inhibiting inflammation in the retinal vasculature.
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