Dataset Information

A new microRNA signal pathway regulated by long noncoding RNA TGFB2-OT1 in autophagy and inflammation of vascular endothelial cells.

ABSTRACT: TGFB2-OT1 (TGFB2 overlapping transcript 1) is a newly discovered long noncoding RNA (lncRNA) derived from the 3'UTR of TGFB2. It can regulate autophagy in vascular endothelial cells (VECs). However, the mechanisms of TGFB2-OT1 action are unclear, and whether it is involved in VECs dysfunction needs investigation. Here, the level of TGFB2-OT1 was markedly increased by lipopolysaccharide and oxidized low-density lipoprotein, 2 VECs inflammation triggers. A chemical small molecule, 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-one (3BDO) significantly decreased TGFB2-OT1 levels and inhibited the effect of LPS and oxLDL. The NUPR1 level was upregulated by the 2 inflammation inducers and modulated the TGFB2-OT1 level by promoting the expression of TIA1, responsible for TGFB2-OT1 processing. We focused on how TGFB2-OT1 regulated autophagy and inflammation. Use of miRNA chip assay, TGFB2-OT1 overexpression technology and 3BDO revealed that TGFB2-OT1 regulated the levels of 3 microRNAs, MIR3960, MIR4488 and MIR4459. Further studies confirmed that TGFB2-OT1 acted as a competing endogenous RNA, bound to MIR3960, MIR4488 and MIR4459, then regulated the expression of the miRNA targets CERS1 (ceramide synthase 1), NAT8L (N-acetyltransferase 8-like [GCN5-related, putative]), and LARP1 (La ribonucleoprotein domain family, member 1). CERS1 and NAT8L participate in autophagy by affecting mitochondrial function. TGFB2-OT1 increased the LARP1 level, which promoted SQSTM1 (sequestosome 1) expression, NFKB RELA and CASP1 activation, and then production of IL6, IL8 and IL1B in VECs. Thus, NUPR1 and TIA1 may control the level of TGFB2-OT1, and TGFB2-OT1 bound to MIR3960, MIR4488 and MIR4459, which targeted CERS1, NAT8L, and LARP1, respectively, the key proteins involved in autophagy and inflammation.

SUBMITTER: Huang S

PROVIDER: S-EPMC4835209 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A new microRNA signal pathway regulated by long noncoding RNA TGFB2-OT1 in autophagy and inflammation of vascular endothelial cells.

Huang ShuYa S Lu Wei W Ge Di D Meng Ning N Li Ying Y Su Le L Zhang ShangLi S Zhang Yun Y Zhao BaoXiang B Miao JunYing J

Autophagy 20150101 12

TGFB2-OT1 (TGFB2 overlapping transcript 1) is a newly discovered long noncoding RNA (lncRNA) derived from the 3'UTR of TGFB2. It can regulate autophagy in vascular endothelial cells (VECs). However, the mechanisms of TGFB2-OT1 action are unclear, and whether it is involved in VECs dysfunction needs investigation. Here, the level of TGFB2-OT1 was markedly increased by lipopolysaccharide and oxidized low-density lipoprotein, 2 VECs inflammation triggers. A chemical small molecule, 3-benzyl-5-((2-n ...[more]

PMID: 26565952

Similar Datasets

Project description:RATIONALE:Microvascular inflammation and endothelial dysfunction secondary to unchecked activation of endothelium play a critical role in the pathophysiology of sepsis and organ failure. The intrinsic signaling mechanisms responsible for dampening excessive activation of endothelial cells are not completely understood. OBJECTIVE:To determine the central role of YAP (Yes-associated protein), the major transcriptional coactivator of the Hippo pathway, in modulating the strength and magnitude of endothelial activation and vascular inflammation. METHODS AND RESULTS:Endothelial-specific YAP knockout mice showed increased basal expression of E-selectin and ICAM (intercellular adhesion molecule)-1 in endothelial cells, a greater number of adherent neutrophils in postcapillary venules and increased neutrophil counts in bronchoalveolar lavage fluid. Lipopolysaccharide challenge of these mice augmented NF-?B (nuclear factor-?B) activation, expression of endothelial adhesion proteins, neutrophil and monocyte adhesion to cremaster muscle venules, transendothelial neutrophil migration, and lung inflammatory injury. Deletion of YAP in endothelial cells also markedly augmented the inflammatory response and cardiovascular dysfunction in a polymicrobial sepsis model induced by cecal ligation and puncture. YAP functioned by interacting with the E3 ubiquitin-protein ligase TLR (Toll-like receptor) signaling adaptor TRAF6 (tumor necrosis factor receptor-associated factor 6) to ubiquitinate TRAF6, and thus promoted TRAF6 degradation and modification resulting in inhibition of NF-?B activation. TRAF6 depletion in endothelial cells rescued the augmented inflammatory phenotype in mice with endothelial cell-specific deletion of YAP. CONCLUSIONS:YAP modulates the activation of endothelial cells and suppresses vascular inflammation through preventing TRAF6-mediated NF-?B activation and is hence essential for limiting the severity of sepsis-induced inflammation and organ failure.

Dataset Information

A new microRNA signal pathway regulated by long noncoding RNA TGFB2-OT1 in autophagy and inflammation of vascular endothelial cells.

Publications

A new microRNA signal pathway regulated by long noncoding RNA TGFB2-OT1 in autophagy and inflammation of vascular endothelial cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets