title: Dehydroepiandrosterone-induced phosphorylation and translocation of FoxO1 depend on the mineralocorticoid receptor.
abstract: In humans, dehydroepiandrosterone (DHEA), with its sulfate, is the most abundant adrenal steroid, whereas the rat adrenals are not capable of synthesizing this steroid. Circulating concentrations of DHEA sulfate lie in the millimolar range and those of DHEA in the subnanomolar range. DHEA exerts protective potential during vascular remodeling, although the underlying mechanisms of this protection are imperfectly defined. We hypothesized that physiological doses of DHEA alter signaling pathways that are of central importance for vascular integrity. We exposed human endothelial cells, vascular smooth muscle cells, and fibroblasts to DHEA (10(-6) to 10(-10) mol/L) and observed a dose- and time-dependent increase of extracellular signal-regulated kinases 1 and 2 activation. Similar results were observed in rat vascular smooth muscle cells. In addition, in rat vascular smooth muscle cells, we found altered phosphorylation and cellular translocation of the transcription factor FoxO1. Pharmacological blockade of the mineralocorticoid receptor (MR) with eplerenone or small interfering RNA-mediated MR-silencing prevented DHEA-induced extracellular signal-regulated kinase 1/2 phosphorylation and its effects on FoxO1. Of note, in a cell-based MR transactivation assay, we did not find any agonist effect of DHEA on MR activity. We conclude that DHEA induces early signaling events in vascular cells that might underlie the DHEA-mediated protection against vasculopathies. These effects are dependent on the MR, although the finding that DHEA fails to act as a direct MR agonist suggests that additional signaling proteins are involved. In this regard, DHEA may either interact with coeffectors to modify MR activity or serves as a ligand for a yet unknown receptor that might transactivate the MR.
authors: Department of Medicine, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
authors: Carsten
authors: C
authors: Lindschau
authors: Torsten
authors: T
authors: Kirsch
authors: Uwe
authors: U
authors: Klinge
authors: Peter
authors: P
authors: Kolkhof
authors: Imke
authors: I
authors: Peters
authors: Anette
authors: A
authors: Fiebeler
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D000077545:Eplerenone; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D018613:Microscopy, Confocal; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D034622:RNA Interference; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism*; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D003687:Dehydroepiandrosterone; D000077545:Eplerenone; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3