Related Experiment Video

Updated: Feb 16, 2026

Analyzing Oxidative Stress in Murine Intestinal Organoids using Reactive Oxygen Species-Sensitive Fluorogenic Probe
09:31

Analyzing Oxidative Stress in Murine Intestinal Organoids using Reactive Oxygen Species-Sensitive Fluorogenic Probe

Published on: September 17, 2021

4.8K

TWEAK/Fn14 promotes oxidative stress through AMPK/PGC‑1α/MnSOD signaling pathway in endothelial cells

Hengdao Liu1, Hui Peng1, Hong Xiang1

  • 1Center for Experimental Medical Research, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China.

Molecular Medicine Reports
|December 20, 2017
PubMed

Insights

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) increases reactive oxygen species (ROS) and mitochondrial ROS (mtROS) in endothelial cells, impairing nitric oxide (NO) production. This dysfunction involves the TWEAK/Fn14 pathway and the AMPK/PGC-1α/MnSOD signaling cascade.

Area of Science:

  • Endothelial cell biology
  • Molecular mechanisms of cell dysfunction
  • Oxidative stress research

Background:

  • Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is known to cause endothelial cell dysfunction via its receptor, Fn14.
  • The specific role of TWEAK/Fn14 in regulating reactive oxygen species (ROS), particularly mitochondrial ROS (mtROS), and nitric oxide (NO) production in endothelial cells is not fully understood.

Purpose of the Study:

  • To investigate the impact of the TWEAK/Fn14 pathway on ROS, mtROS, and NO generation in human umbilical vein endothelial cells (HUVECs).
  • To elucidate the underlying molecular mechanisms, including the involvement of the AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)/manganese superoxide dismutase (MnSOD) signaling pathway.

Main Methods:

  • Human umbilical vein endothelial cells (HUVECs) were treated with TWEAK and Fn14 small interfering (si)RNA or control RNA.
  • ROS and mtROS production were assessed using fluorescent microscopy and flow cytometry.
  • Nitric Oxide (NO) levels were measured using a Nitric Oxide Assay kit.
  • Mitochondrial DNA (mtDNA) damage was quantified via polymerase chain reaction (PCR).
  • Protein expression levels of active AMPK, PGC-1α, and MnSOD were analyzed.

Main Results:

  • TWEAK significantly increased ROS and mtROS production and aggravated mtDNA damage in HUVECs.
  • TWEAK treatment led to a decrease in NO generation.
  • Inhibition of Fn14 using siRNA counteracted TWEAK-induced ROS and mtROS production and mtDNA damage, while restoring NO levels.
  • TWEAK inhibited the expression of active AMPK, PGC-1α, and MnSOD; Fn14 siRNA reversed these inhibitory effects.

Conclusions:

  • The TWEAK/Fn14 pathway contributes to endothelial dysfunction by modulating ROS and mtROS production.
  • The underlying mechanism involves the disruption of the AMPK/PGC-1α/MnSOD signaling pathway.
  • Targeting the TWEAK/Fn14 interaction may offer a therapeutic strategy for endothelial dysfunction associated with oxidative stress.

More Related Videos

En Face Detection of Nitric Oxide and Superoxide in Endothelial Layer of Intact Arteries08:58

En Face Detection of Nitric Oxide and Superoxide in Endothelial Layer of Intact Arteries

Published on: February 25, 2016

10.1K
Measurements of Physiological Stress Responses in C. Elegans10:36

Measurements of Physiological Stress Responses in C. Elegans

Published on: May 21, 2020

15.1K

Related Concept Videos

Nitric Oxide Signaling Pathway01:28

Nitric Oxide Signaling Pathway

Nitric oxide (NO), an inorganic gas, acts as a potent second messenger in most animal and plant tissues. NO diffuses out of the cells that produce it and enters the neighboring cells to generate a downstream response. NO synthase (NOS) catalyzes NO production by the deamination of the amino acid arginine. There are three isoforms of NOS. Endothelial cells have endothelial NOS (eNOS), nerve and muscle cells have neuronal NOS (nNOS), and macrophages produce inducible NOS (iNOS) upon exposure...
6.4K
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
3.1K