Author + information
- Frank Spillmann,
- Sophie van Linthout,
- Kapka Miteva,
- Mario Lorenz,
- Verena Stangl,
- Heinz-Peter Schultheiss and
- Carsten Tschöpe
Inflammation is a major trigger of endothelial dysfunction. On the other hand, LXR agonists have anti-inflammatory properties. Therefore, we aimed to investigate whether supplementation of the LXR agonist T0901317 could improve TNF-α-induced endothelial dysfunction.
HUVEC were stimulated with or without 10 ng/ml of TNF-α in the presence or absence of 5 ?? of the LXR agonist T0901317 for 30 minutes for mRNA expression and 1 or 2 hours for enzyme activity and protein expression analysis. Endothelium-dependent vasorelaxation of aortic rings was determined in an organ water bath.
T091317 reduced the TNF-α-upregulated NOX4 and p22phox mRNA expression in HUVEC by 1.7-fold (P<0.05) and 2.9-fold (P<0.05), respectively, and normalized the TNF-α-induced NOX activity by 1.5-fold (P<0.01) to basal levels. Concomitantly, T091317 decreased the TNF-α-upregulated arginase activity by 4.2-fold (P<0.01), whereas it reversed TNF-α-induced downregulation of argininosuccinate synthase mRNA expression to basal levels. In parallel, T091317 normalized TNF-α-induced downregulation in eNOS expression to basal levels. In agreement with these findings, T091317 raised the TNF-α-impaired NO production by 1.9-fold (P<0.05 vs TNF-α). Furthermore, it restored eNOS uncoupling as suggested by the 1.4-fold drop in TNF-α-induced nitrotyrosine (P<0.005 vs TNF-α) and the raise in eNOS dimer to monomer ratio. Finally, T091317 improved TNF-α-impaired endothelium-dependent relaxation in response to acetylcholine in aortic rings (P<0.05 vs TNF-α).
LXR agonism improves TNF-α-impaired endothelial function via its anti-oxidative properties and its capacity to induce eNOS expression and to decrease eNOS uncoupling, restoring the TNF-α-decreased NO bioavailability.
Poster Sessions, Expo North
Saturday, March 09, 2013, 3:45 p.m.-4:30 p.m.
Session Title: Novel Therapeutic Targets in Hearts Failure
Abstract Category: 16. Heart Failure: Basic
Presentation Number: 1176-294
- 2013 American College of Cardiology Foundation