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

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

Author information

1
Department of Cardiology and Pneumology, Charité - University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany.
2
Berlin-Brandenburg Center for Regenerative Therapies, Charité - University Medicine Berlin, Campus Virchow, Berlin, Germany.
3
Department of Cardiology and Angiology, Charité - University Medicine Berlin, Campus Mitte, Berlin, Germany; DZHK (German Center for Cardiovascular Research), Berlin, Germany.
4
Department of Cardiology and Pneumology, Charité - University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies, Charité - University Medicine Berlin, Campus Virchow, Berlin, Germany; DZHK (German Center for Cardiovascular Research), Berlin, Germany. Electronic address: carsten.tschoepe@charite.de.

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.

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

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