title: 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.
authors.affiliation: Department of Cardiology and Pneumology, Charité - University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Spillmann
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies, Charité - University Medicine Berlin, Campus Virchow, Berlin, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Van Linthout
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies, Charité - University Medicine Berlin, Campus Virchow, Berlin, Germany.
authors.forename: Kapka
authors.initials: K
authors.lastname: Miteva
authors.affiliation: Department of Cardiology and Angiology, Charité - University Medicine Berlin, Campus Mitte, Berlin, Germany; DZHK (German Center for Cardiovascular Research), Berlin, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Lorenz
authors.affiliation: Department of Cardiology and Angiology, Charité - University Medicine Berlin, Campus Mitte, Berlin, Germany; DZHK (German Center for Cardiovascular Research), Berlin, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Stangl
authors.affiliation: Department of Cardiology and Pneumology, Charité - University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.affiliation: 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.
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001011:Aorta / Q000378:metabolism; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D004727:Endothelium / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D066298:In Vitro Techniques; D000071518:Liver X Receptors; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000378:metabolism; D018384:Oxidative Stress; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D013449:Sulfonamides / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D000975:Antioxidants; D001565:Benzoates; D001596:Benzylamines; D053148:Caspase 3; D053179:Caspase 7; D002784:Cholesterol; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D019255:NADPH Oxidases; D009569:Nitric Oxide; D057093:Orphan Nuclear Receptors; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C473027:GW 3965; C000605213:NR1H3 protein, human; C000605215:Nr1h3 protein, rat; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
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