LXR agonism improves TNF-α-induced endothelial dysfunction in the absence of its cholesterol-modulating effects

Atherosclerosis. 2014 Jan;232(1):1-9. doi: 10.1016/j.atherosclerosis.2013.10.001. Epub 2013 Oct 26.


Stimulation of the liver X receptor (LXR) is associated with anti-inflammatory and vascular-protective effects under hyperlipemic conditions. We examined whether LXR stimulation influences TNF-α-induced endothelial dysfunction under normolipemic conditions. Endothelium-dependent vasorelaxation of aortic rings was determined in an organ water bath. Human umbilical vein endothelial cells (HUVEC) were exposed to TNF-α (10 ng/ml) in the presence or absence of 5 μM of the LXR agonist T0901317 or GW3965 and changes in TNF-α-induced endothelial cell apoptosis, inflammation, oxidative stress, and NO metabolism were analyzed. T0901317 improved TNF-α-impaired endothelium-dependent relaxation of aortic rings in response to acetylcholine. T0901317 decreased the TNF-α-induced apoptosis and inflammation as indicated by a decrease in caspase 3/7 activity, VCAM-1 mRNA expression and subsequent mononuclear cell adhesion. Furthermore, T0901317 reduced the expression of the oxidative stress markers: AT1R, NOX4, and p22phox and normalized the TNF-α-induced NOX activity to basal levels. In line with the reduced AT1R expression, T0901317 impaired the Ang II responsiveness. T0901317 influenced NO metabolism as indicated by a decrease in TNF-α-upregulated arginase activity, a reversal of TNF-α-induced downregulation of argininosuccinate synthase mRNA expression and eNOS expression to basal levels and a raise in NO production. Furthermore, T0901317 decreased the TNF-α-induced superoxide and nitrotyrosine production, but did not upregulate the TNF-α-downregulated eNOS dimer/monomer ratio. Silencing of LXRβ, but not of LXRα, abrogated the anti-apoptotic effects of T0901317. We conclude that LXR agonism improves TNF-α-impaired endothelial function via its anti-apoptotic, anti-inflammatory, and anti-oxidative properties and its capacity to restore TNF-α-impaired NO bioavailability independent of its cholesterol-modulating effects.

Keywords: Endothelial dysfunction; HUVEC; LXR; LXR agonist; Liver X receptor; NAD(P)H oxidase; NO; NOX; Nitric oxide; O(2)•; ROS; RXR; TNF; TNF-α; eNOS; endothelial nitric oxide synthase; human umbilical vein cells; nitric oxide; reactive oxygen species; retinoid X receptor; superoxide; tumor necrosis factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Aorta / metabolism
  • Benzoates / pharmacology
  • Benzylamines / pharmacology
  • Caspase 3 / metabolism
  • Caspase 7 / metabolism
  • Cholesterol / metabolism*
  • Endothelium / drug effects
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Hydrocarbons, Fluorinated / pharmacology*
  • In Vitro Techniques
  • Liver X Receptors
  • Male
  • NADPH Oxidases / metabolism
  • Nitric Oxide / metabolism
  • Orphan Nuclear Receptors / agonists*
  • Orphan Nuclear Receptors / metabolism
  • Oxidative Stress
  • RNA, Small Interfering / metabolism
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species
  • Sulfonamides / pharmacology*
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Antioxidants
  • Benzoates
  • Benzylamines
  • GW 3965
  • Hydrocarbons, Fluorinated
  • Liver X Receptors
  • NR1H3 protein, human
  • Nr1h3 protein, rat
  • Orphan Nuclear Receptors
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Sulfonamides
  • T0901317
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • Cholesterol
  • NADPH Oxidases
  • Caspase 3
  • Caspase 7