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Cardiovasc Res. 2012 Jul 1;95(1):97-107. doi: 10.1093/cvr/cvs149. Epub 2012 Apr 16.

Relaxin improves TNF-α-induced endothelial dysfunction: the role of glucocorticoid receptor and phosphatidylinositol 3-kinase signalling.

Author information

1
Immundiagnostik AG, Stubenwaldallee 8a, Bensheim, Germany.

Abstract

AIMS:

Human relaxin-2 influences renal and cardiovascular functions. We investigated its effects on experimental endothelial dysfunction.

METHODS AND RESULTS:

Acetylcholine-mediated vasodilation of rat aortic rings, impaired by 48 h tumour necrosis factor-α (TNF-α) treatment, was dose-dependently improved by relaxin co-incubation, an effect sensitive to phosphatidylinositol 3-kinase (PI3K) inhibition and the glucocorticoid receptor (GR) antagonist RU-486. TNF increased endothelial nitric oxide synthase (eNOS) phosphorylation at Thr495 and decreased total eNOS expression and both 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. Via GR, relaxin attenuated the TNF-related stimulation of endothelin-1 expression, superoxide and nitrotyrosine formation, and arginase II expression. Relaxin restored, via GR-CCAAT/enhancer-binding protein-β (c/EBP-β)-mediated promoter stimulation, the compromised expression of superoxide dismutase-1 (SOD1). In rat aortic endothelial cells, relaxin activated protein kinase B (Akt) and repressed TNF-induced nuclear factor-κB and activator protein-1. Finally, the relevance of the different findings to the model used was proved by pharmacological interventions.

CONCLUSION:

Relaxin improved endothelial dysfunction by promoting eNOS activity, suppressing endothelin-1 and arginase-II expression, and up-regulating SOD1 via GR, GR-c/EBP-β, and PI3K-Akt pathways. This corroborates the notion that it functions as an endogenous and potentially therapeutic vasoprotector.

PMID:
22510373
DOI:
10.1093/cvr/cvs149
[Indexed for MEDLINE]

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