TRAIL protects against endothelial dysfunction in vivo and inhibits angiotensin-II-induced oxidative stress in vascular endothelial cells in vitro

Free Radic Biol Med. 2018 Oct:126:341-349. doi: 10.1016/j.freeradbiomed.2018.08.031. Epub 2018 Aug 27.


The vascular endothelium is critical for maintenance of cardiovascular homeostasis. Endothelial dysfunction is a key event of atherosclerosis, with oxidative stress mediated by reactive oxygen species (ROS) playing a major role. Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is increasingly recognised to play a protective role in atherosclerosis, however the molecular mechanisms by which it exerts its beneficial effects are unclear. Here we examined if TRAIL could attenuate vascular oxidative stress and improve endothelial cell (EC) function. In coronary artery disease patients, plasma TRAIL levels were significantly reduced compared to healthy individuals, and negatively correlated with the levels of circulating 8-iso Prostaglandin F, a marker of in vivo oxidative stress. In vivo, high-fat fed, atherosclerotic Trail-/-Apoe-/- mice exhibited a significant impairment in endothelial-dependent vasorelaxation, which correlated with increased vascular ROS and 4-hydroxynonenal compared to Apoe-/- mice. Endothelial permeability measured by Evan's blue dye extravasation was increased in several organs of Trail-/- mice compared to wild-type mice, which correlated with a decrease in VE-cadherin expression. In vitro in ECs, angiotensin II (AngII)-induced ROS generation involving the mitochondria, NADPH oxidase-4 (NOX-4) and eNOS, was inhibited by pre-treatment with TRAIL. Furthermore, AngII-augmented VCAM-1 expression and monocyte adhesion to ECs was inhibited by TRAIL. Finally, AngII reduced VE-cadherin expression and redistributed this protein, all of which was brought back to baseline by TRAIL pre-treatment. These findings demonstrate for the first time that TRAIL protects against several forms of endothelial dysfunction involving its ability to control EC ROS generation. Understanding the role TRAIL plays in normal physiology and disease, may lead to potential new therapies to improve endothelial function and atherosclerosis.

Keywords: Angiotensin II; Endothelial cells; Oxidative stress; TRAIL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / metabolism
  • Angiotensin II / genetics
  • Angiotensin II / metabolism
  • Animals
  • Apolipoproteins E / genetics
  • Atherosclerosis / genetics*
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Diet, High-Fat / adverse effects
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Humans
  • Mice
  • Nitric Oxide Synthase Type III / genetics
  • Oxidative Stress / genetics*
  • Reactive Oxygen Species / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / administration & dosage
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Vascular Cell Adhesion Molecule-1 / genetics
  • Vasodilation / genetics*


  • Aldehydes
  • Apolipoproteins E
  • Reactive Oxygen Species
  • TNF-Related Apoptosis-Inducing Ligand
  • Vascular Cell Adhesion Molecule-1
  • Angiotensin II
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III
  • 4-hydroxy-2-nonenal