Abstract 12951: Relaxin Improves Experimentally Induced Endothelial Dysfunction Via Phosphatidylinositol 3-Kinase Signaling and Glucocorticoid Receptor-Mediated Effects
Introduction: The insulin-like peptide relaxin exerts, next to its role in human reproduction, a multiplicity of functions as a vasodilatory, anti-fibrotic, diuretic and positive inotropic player in the human organism. Signal transduction mediated by G protein-coupled RXFP1 receptors but also by activation of the human glucocortocoid receptor (GR) has recently been described. We previously identified relaxin as a compensatory factor in human heart failure. A clinical trial in patients with acute decompensated heart failure is currently under way. Here, we investigated whether relaxin could improve TNF-α-induced endothelial dysfunction and provided insight into the underlying signal transduction pathways.
Methods and results: Acetylcholine-mediated vasodilation of rat aortic rings was markedly perturbed by 48-hour TNF-α treatment; co-incubation with relaxin dose-dependently ameliorated TNF-α-induced dysfunction, this effect being sensitive to the PI3K inhibitor wortmannin and the glucocorticoid receptor (GR) antagonist RU-486. TNF increased eNOS phosphorylation at Thr495 and decreased total eNOS expression as well as basal and stimulated eNOS activity. Relaxin co-incubation did not affect eNOS expression but improved its activity via PI3K-dependent Thr495 dephosphorylation and Ser1177 phosphorylation, and additional Ser633 phosphorylation. Relaxin furthermore attenuated the TNF-related stimulation of endothelin-1 expression, an effect sensitive to RU-486. TNF-α-induced oxidative stress, indicated by enhanced superoxide and nitrotyrosine formation as well as increased arginase II activity and expression, was reduced by relaxin in a GR-dependent manner. Relaxin also restored the compromised expression of superoxide dismutase-1. In additional cell experiments, relaxin was shown to activate the PI3K-Akt axis and to repress TNF-induced activation of NF-kappaB.
Conclusion: Relaxin was shown to remarkably ameliorate TNF-α-mediated endothelial dysfunction via GR-mediated inhibition of NF-kappaB-induced signaling (transrepression) and via PI3K-mediated activation of PI3K-Akt-eNOS pathway. This confirms relaxin's potential as a new promising candidate drug for vascular protection.
- © 2011 by American Heart Association, Inc.