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.

DNA Methylation Dynamics in Human Carotid Plaques After Cerebrovascular Events

“…Another example is the myocyte enhancer factor 2 C (MEF2C), a suppressor of the inflammatory response. 23 These findings suggested that other genes involved in the control of cellular oxidation reactions underwent similar epigenetic changes. Indeed, the analysis of the initial 45 214 PCET-CpG set revealed that known players in cellular defense against oxidation-that is, members of the glutathione peroxidase (GPX), superoxide dismutase (SOD), thioredoxin reductase (TXNRD), and thioredoxin (TXN) families [24][25][26] were hypomethylated at their promoters with increasing PCET.…”

Endothelial Myocyte Enhancer Factor 2c Inhibits Migration of Smooth Muscle Cells Through Fenestrations in the Internal Elastic Lamina

“…These experiments show that Mef2c is important for protection to hyperoxia and pathological angiogenesis, partly through Hmox1 regulation 28 . They further revealed a protective role for Mef2c in inflammation in that LPS-induced leukocyte adhesion in retinal vessels is increased in Mef2c deleted endothelium 15 . While deletion of Mef2c alone did not affect angiogenesis, combined endothelial-specific deletion of Mef2a and -c revealed that they regulate angiogenic sprouting and are direct transcriptional regulators of Dll4 in angiogenic tip cells 29 .…”

“…The four Mef2s (Mef2a - d) are important transcriptional regulators in a number of cell types that can activate or repress transcription depending on modifications and interacting partners 12–14 . The most studied in vitro targets for Mef2 in ECs are Klf2 and Klf4, which regulate an anti-thrombotic and anti-inflammatory transcriptional program 15–21 . Two stimuli that protect against atherosclerosis increase the ability of Mef2 to activate transcription in vitro: LF and statins.…”

“…In vivo experiments supporting a role for Mef2 in the endothelium have been restricted to the retinal vasculature and developing embryo 15,28,29 . These experiments show that Mef2c is important for protection to hyperoxia and pathological angiogenesis, partly through Hmox1 regulation 28 .…”

Epigenetic Mechanisms Regulating the Functional Effects of Chronic Alcohol Exposure of Human Monocyte-derived Dendritic Cells

“…Once promoters are available, transcription factors along with RNA polymerase II can bind to promoters which leads to gene expression (Stasevich et al, 2014). Certain groups of transcription factors are important players in inflammation like HIF (hypoxia-inducible factor) (Palazon et al, 2014), Egr2 and Egr 3 in B and T cells , MEF2c, NFκB and KLF2 (Xu et al, 2015). The study of these transcription factors, may help further understanding the role of alcohol induced H4k12ac in regulating inflammation and oxidative stress.…”