当前位置： SCI文献检索 > ATHEROSCLEROSIS期刊下所有文献 > LXR agonism improves TNF-α-induced endothelial dysfunction in the absence of its cholesterol-modulating effects.

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

Abstract：

: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.

journal_name

Atherosclerosis

journal_title

Atherosclerosis

authors

Spillmann F,Van Linthout S,Miteva K,Lorenz M,Stangl V,Schultheiss HP,Tschöpe C

doi

10.1016/j.atherosclerosis.2013.10.001

subject

Has Abstract

pub_date

2014-01-01 00:00:00

pages

1-9

issue

eissn

0021-9150

issn

1879-1484

pii

S0021-9150(13)00594-7

journal_volume

232

pub_type

杂志文章

在线工具

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