TFEB inhibits endothelial cell inflammation and reduces atherosclerosis

Abstract

Transcription factor EB (TFEB) is a master regulator of autophagy and lysosome biogenesis. We investigated the function of TFEB in vascular biology and pathophysiology and demonstrated that TFEB in endothelial cells inhibited inflammation and reduced atherosclerosis development. Laminar shear stress, which protects against atherosclerosis, increased TFEB abundance in cultured primary human endothelial cells. Furthermore, TFEB overexpression in these cells was anti-inflammatory, whereas TFEB knockdown aggravated inflammation. The anti-inflammatory effect of TFEB was, at least, partially due to reduced oxidative stress because TFEB overexpression in endothelial cells decreased the concentrations of reactive oxygen species and increased the expression of the antioxidant genes HO1 (which encodes heme oxygenase 1) and SOD2 (which encodes superoxide dismutase 2). In addition, transgenic mice with endothelial cell-specific expression of TFEB exhibited reduced leukocyte recruitment to endothelial cells and decreased atherosclerosis development. Our study suggests that TFEB is a protective transcription factor against endothelial cell inflammation and a potential target for treating atherosclerosis and associated cardiovascular diseases.

Reactive Oxygen Species Generation and Atherosclerosis

“…Laminar shear stress increases expression of transcription factor EB (TFEB) in cultured human ECs. 55 TFEB is a basic helix-loop-helix transcription factor, which regulates lysosomal biogenesis. 56 Laminar shear stress induced TFEB translocation to the nucleus and decreased mTOR (mechanistic target of rapamycin) activity in ECs.…”

TFEB controls vascular development by regulating the proliferation of endothelial cells

“…Furthermore, TFEB controls lipid breakdown, and its overexpression activates fatty acid oxidation (Settembre et al, 2013a), which is necessary for sprouting angiogenesis, by fueling de novo nucleotide synthesis for DNA duplication (Schoors et al, 2015). Furthermore, the recent observation that shear stress up-regulates TFEB (Lu et al, 2017) allows hypothesizing its role in regulating the optimal PM amount of VEGFR2, which, through a multimeric complex with VE-cadherin, PECAM-1, and VEGFR3 (Baeyens et al, 2016), transduces the frictional force from blood flow into biochemical signals that regulate gene expression and cell behavior. To generate transgenic mice expressing Tfeb-GFP, the sequence for the open reading frame of EGFP was inserted between the last amino acid and the translation termination codon in exon 9 (NCBI transcript NM_001161722.1).…”

Krüppel-like factor 14, a coronary artery disease associated transcription factor, inhibits endothelial inflammation via NF-κB signaling pathway

“…Next we performed leukocyte adhesion assays both in vitro and in vivo to investigate whether KLF14 contribution to this process 18 . In Fig.…”

“…Intravital microscopy analysis was performed as previously described 18 . There were two experimental approaches in this study.…”