Dehydroepiandrosterone protects vascular endothelial cells against apoptosis through a Galphai protein-dependent activation of phosphatidylinositol 3-kinase/Akt and regulation of antiapoptotic Bcl-2 expression

Dongmin Liu; Hongwei Si; Kathryn A Reynolds; Wei Zhen; Zhenquan Jia; Joseph S Dillon

doi:10.1210/en.2006-1378

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Dehydroepiandrosterone protects vascular endothelial cells against apoptosis through a Galphai protein-dependent activation of phosphatidylinositol 3-kinase/Akt and regulation of antiapoptotic Bcl-2 expression

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Dehydroepiandrosterone protects vascular endothelial cells against apoptosis through a Galphai protein-dependent activation of phosphatidylinositol 3-kinase/Akt and regulation of antiapoptotic Bcl-2 expression

Dongmin Liu, Hongwei Si, Kathryn A Reynolds, Wei Zhen, Zhenquan Jia and Joseph S Dillon

Endocrinology (Philadelphia), Vol.148(7), pp.3068-3076

07/2007

DOI: 10.1210/en.2006-1378

PMID: 17395704

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Abstract

The adrenal steroid dehydroepiandrosterone (DHEA) may improve vascular function, but the mechanism is unclear. In the present study, we show that DHEA significantly increased cell viability, reduced caspase-3 activity, and protected both bovine and human vascular endothelial cells against serum deprivation-induced apoptosis. This effect was dose dependent and maximal at physiological concentrations (0.1-10 nM). DHEA stimulation of bovine aortic endothelial cells resulted in rapid and dose-dependent phosphorylation of Akt, which was blocked by LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K), the upstream kinase of Akt. Accordingly, inhibition of PI3K or transfection of the cells with dominant-negative Akt ablated the antiapoptotic effect of DHEA. The induced Akt phosphorylation and subsequent cytoprotective effect of DHEA were dependent on activation of Galphai proteins, but were estrogen receptor independent, because these effects were blocked by pertussis toxin but not by the estrogen receptor inhibitor ICI182,780 or the aromatase inhibitor aminoglutethimide. Finally, DHEA enhanced antiapoptotic Bcl-2 protein expression, its promoter activity, and gene transcription attributable to the activation of the PI3K/Akt pathway. Neutralization of Bcl-2 by antibody transfection significantly decreased the antiapoptotic effect of DHEA. These findings provide the first evidence that DHEA acts as a survival factor for endothelial cells by triggering the Galphai-PI3K/Akt-Bcl-2 pathway to protect cells against apoptosis. This may represent an important mechanism underlying the vascular protective effect of DHEA.

Cell Survival - drug effects

Estradiol - metabolism

Temperature

Gene Expression - drug effects

Apoptosis - drug effects

Dehydroepiandrosterone - pharmacology

Endothelial Cells - metabolism

Humans

Caspase 3 - metabolism

Cells, Cultured

Endoplasmic Reticulum - metabolism

Immunoblotting

Phosphatidylinositol 3-Kinases - metabolism

Reverse Transcriptase Polymerase Chain Reaction

Proto-Oncogene Proteins c-akt - genetics

Proto-Oncogene Proteins c-bcl-2 - metabolism

Animals

Time Factors

Cattle

Endothelial Cells - cytology

Phosphorylation - drug effects

Proto-Oncogene Proteins c-akt - metabolism

Proto-Oncogene Proteins c-bcl-2 - genetics

Endothelial Cells - drug effects

Details

Title: Subtitle: Dehydroepiandrosterone protects vascular endothelial cells against apoptosis through a Galphai protein-dependent activation of phosphatidylinositol 3-kinase/Akt and regulation of antiapoptotic Bcl-2 expression
Creators: Dongmin Liu - Department of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24060, USA. doliu@vt.edu
Hongwei Si
Kathryn A Reynolds
Wei Zhen
Zhenquan Jia
Joseph S Dillon
Resource Type: Journal article
Publication Details: Endocrinology (Philadelphia), Vol.148(7), pp.3068-3076
DOI: 10.1210/en.2006-1378
PMID: 17395704
NLM abbreviation: Endocrinology
ISSN: 0013-7227
eISSN: 1945-7170
Grant note: R01 AG018928 / NIA NIH HHS R01AG55741 / NIA NIH HHS
Language: English
Date published: 07/2007
Academic Unit: Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984094725102771

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