Dehydroepiandrosterone Stimulates Phosphorylation of FoxO1 in Vascular Endothelial Cells via Phosphatidylinositol 3-Kinase- and Protein Kinase A-dependent Signaling Pathways to Regulate ET-1 Synthesis and Secretion

Chen, Hui; Lin, Alice Seraphina; Li, Yunhua; Reiter, Chad E.N.; Ver, Maria R.; Quon, Michael J.

doi:10.1074/jbc.m802906200

Cited by 40 publications

(32 citation statements)

References 70 publications

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“…A DHEA receptor has been described, which is coupled to endothelial nitric oxide synthase, and DHEA has also been shown to regulate vascular endothelin-1 synthesis and secretion (34,35). Lower levels of circulating DHEA-S in our cases as compared with control subjects may contribute to down-regulation of nitric oxide and enhanced endothelin activation, two major pathophysiologic drivers in pulmonary vascular disease.…”

Section: Original Articlementioning

confidence: 69%

Higher Estradiol and Lower Dehydroepiandrosterone-Sulfate Levels Are Associated with Pulmonary Arterial Hypertension in Men

Ventetuolo

Baird

Barr

et al. 2016

Am J Respir Crit Care Med

112

111

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Rationale: Recent studies have focused on the role of female sex and estradiol (E2) in pulmonary arterial hypertension (PAH), but it is not known whether sex hormones are risk factors for PAH in men.Objectives: We performed a case-control study to determine whether hormone levels (E2, dehydroepiandrosterone-sulfate [DHEA-S], and testosterone) are associated with PAH in men.Methods: Plasma sex hormone levels in men with idiopathic, heritable, or connective tissue disease-associated PAH were compared with those from age-and body mass index-matched men without clinical cardiovascular disease.Measurements and Main Results: There were 23 cases with PAH (70% had idiopathic PAH, 65% were functional class III/IV) and 67 control subjects. Higher E2 and E2/testosterone levels were associated with the risk of PAH (odds ratio per 1 ln[E2:testosterone], 6.0; 95% confidence interval, 2.2-16.4; P = 0.001), whereas higher levels of DHEA-S were associated with a reduced risk (odds ratio per 1 ln[DHEA-S], 0.1; 95% confidence interval, 0.0-0.3; P = 0.001). E2 and DHEA-S levels were strong predictors of case status (C statistic for both, 0.82) but testosterone was not (C statistic, 0.53). Higher levels of E2 were associated with shorter 6-minute-walk distances (P = 0.03), whereas higher levels of DHEA-S were associated with lower right atrial pressure (P = 0.02) and pulmonary vascular resistance (P = 0.01) in men with PAH.Conclusions: Higher levels of E2 and lower levels of DHEA-S were associated with PAH in men. Sex-based differences in sex hormone processing and signaling may contribute to unique phenotypes in pulmonary vascular disease.

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Section: Original Articlementioning

confidence: 69%

Higher Estradiol and Lower Dehydroepiandrosterone-Sulfate Levels Are Associated with Pulmonary Arterial Hypertension in Men

Ventetuolo

Baird

Barr

et al. 2016

Am J Respir Crit Care Med

112

111

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“…and vascular homeostasis in response to insulin and other growth factors (1)(2)(3). Mice lacking FoxO1 die in utero from improper vascular development (4).…”

mentioning

confidence: 99%

“…Cell Culture-Bovine aortic endothelial cells (BAEC) (Cell Applications, San Diego, CA) or human aortic endothelial cells (HAEC) (Lonza, Walkersville, MD) in primary culture were grown in endothelial growth medium EGM-MV (BAEC; Lonza) or EGM-2 (HAEC; Lonza) and used between passages 3 and 6 as described previously (3). Endothelial cells were grown in 60-mm dishes and serum-starved overnight (BAEC) or for 6 h (HAEC) in endothelial basal medium (Lonza).…”

mentioning

confidence: 99%

Protein Kinase A-α Directly Phosphorylates FoxO1 in Vascular Endothelial Cells to Regulate Expression of Vascular Cellular Adhesion Molecule-1 mRNA

Lee

Chen

Pullikotil

et al. 2011

Journal of Biological Chemistry

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Forkhead box O1 (FoxO1) is a member of the FoxO transcription factor family that plays important roles in regulation of glucose homeostasis, cellular proliferation, differentiation, and vascular homeostasis in response to insulin and other growth factors (1-3). Mice lacking FoxO1 die in utero from improper vascular development (4). Overexpression of FoxO1 in primary endothelial cells impairs cell migration and tube formation, whereas knockdown of FoxO1 using siRNA enhances angiogenic function (5). Moreover, siRNA knockdown of FoxO1 in human coronary artery endothelial cells reduces VEGF-induced vascular cellular adhesion molecule-1 (VCAM-1) 2 expression and monocyte adhesion to endothelial cells (6). FoxO1 function is regulated, in part, by post-translational modifications including phosphorylation, acetylation, and ubiquitination (7-9). Phosphorylation of FoxO1 at a number of specific regulatory sites results in translocation of FoxO1 from the nucleus to the cytosol that impairs its transcriptional activity (2). Akt, a serine/threonine kinase downstream from PI3K in insulin signaling pathways, phosphorylate FoxO1 at Thr 24 , Ser 256 , and Ser 319 to promote nuclear exclusion of FoxO1. Thus, insulin negatively regulates FoxO1 functions via phosphorylation by Akt (10, 11). In addition to Akt, other kinases including SGK phosphorylate FoxO1 to regulate its function in a similar manner. For example, SGK phosphorylates FoxO1 at Thr 24 and Ser 319 (11,12). Similar to Akt, SGK is activated by a variety of growth and survival factors including insulin (13,14). cAMP-dependent protein kinase (PKA) is a key regulator of many processes involved with cell growth and development. PKA is activated when cAMP binds to the regulatory subunit of PKA, resulting in release of the catalytic subunit that then phosphorylates a variety of protein substrates including ion channels, key metabolic enzymes, and transcription factors (15).In a previous study, we reported that dihydroepiandrosterone treatment of primary endothelial cells acutely increases phosphorylation of FoxO1 in a PKA-dependent manner to reduce expression of ET-1 by interfering with the binding of FoxO1 to the human ET-1 promoter (3). Therefore, in the present study, we tested the hypothesis that FoxO1 is a novel direct substrate for PKA-␣ that helps to regulate endothelial function in response to activation of PKA-␣.

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“…19 Therefore, a model was drawn of different DHEA signaling pathways leading either to vasodilation via phosphatidylinositol 3-kinase and endothelial NO synthase or vasoconstriction via mitogen-activated protein kinase kinase/ protein kinase A-FoxO1-endothelin 1. 18 In VSMCs, Abid et al 20 found that active FoxO inhibited proliferation, and the authors concluded that FoxOs might be a therapeutic target in vasculopathic states. We identified MR to be crucial for transmitting the signaling response to DHEA (Figure 6).…”

Section: Hypertension September 2011mentioning

confidence: 99%

“…The underlying mechanisms and their consequence remain to be clarified. To shed more light on DHEA-induced signaling, Chen et al 18 investigated endothelial cells and observed DHEAinduced phosphorylation of the forkhead transcription factor FoxO1, which depends on ERK1/2. In addition, these authors demonstrated that a DHEA-induced signaling cascade via FoxO1 leads to increased expression of the vasoconstrictor endothelin 1.…”

Section: Hypertension September 2011mentioning

confidence: 99%

Dehydroepiandrosterone-Induced Phosphorylation and Translocation of FoxO1 Depend on the Mineralocorticoid Receptor

Lindschau

Kirsch²,

Klinge³

et al. 2011

Hypertension

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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 Ϫ6 to 10 Ϫ10 mol/L) and observed a doseand 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. , with its conjugated sulfate, is the most abundant adrenal steroid in humans, whereas rat adrenals do not make this steroid. In humans, circulating levels of DHEA sulfate are in the millimolar range and those of DHEA are in the subnanomolar range. Numerous studies have reported its protective capabilities in terms of general mortality and, in particular, in cardiovascular disease, which is characterized by progressive vascular remodeling, a leading cause of age-related morbidity and mortality. BarrettConnor et al 1 demonstrated that reduced concentrations of circulating DHEA sulfate represent an independent marker for prediction of mortality in general, as well as death from cardiovascular diseases in particular. Other groups found similar results. [2][3][4][5] The mode of action of DHEA and its related signaling pathways have remained largely ill defined. During human lifetime, circulating concentrations of DHEA and DHEA sulfate decline from peak levels in the 20s to 10% to 20% in the 70s, and the incidence of inflammatory and malignant processes is inversely correlated with a decline in circulating concentrations of DHEA. 6,7 Circulating hormones first contact the vascular endothelium, which plays a crucial role in vascular remodeli...

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Dehydroepiandrosterone Stimulates Phosphorylation of FoxO1 in Vascular Endothelial Cells via Phosphatidylinositol 3-Kinase- and Protein Kinase A-dependent Signaling Pathways to Regulate ET-1 Synthesis and Secretion

Cited by 40 publications

References 70 publications

Higher Estradiol and Lower Dehydroepiandrosterone-Sulfate Levels Are Associated with Pulmonary Arterial Hypertension in Men

Higher Estradiol and Lower Dehydroepiandrosterone-Sulfate Levels Are Associated with Pulmonary Arterial Hypertension in Men

Protein Kinase A-α Directly Phosphorylates FoxO1 in Vascular Endothelial Cells to Regulate Expression of Vascular Cellular Adhesion Molecule-1 mRNA

Dehydroepiandrosterone-Induced Phosphorylation and Translocation of FoxO1 Depend on the Mineralocorticoid Receptor

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