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Dehydroepiandrosterone Protects Vascular Endothelial Cells against Apoptosis through a G_i Protein-Dependent Activation of Phosphatidylinositol 3-Kinase/Akt and Regulation of Antiapoptotic Bcl-2 Expression

Departments of Human Nutrition, Foods, and Exercise (D.L., H.S., K.A.R., W.Z.) and Biomedical Sciences and Pathobiology (Z.J.), Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061; and Iowa City Veterans Affairs Medical Center and Division of Endocrinology (J.S.D.), Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242

Address all correspondence and requests for reprints to: Dongmin Liu, Ph.D., Department of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24060. E-mail: doliu{at}vt.edu; or Joseph S. Dillon, M.D., Iowa City Veterans Affairs Medical Center and Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242. E-mail: joseph-dillon{at}uiowa.edu.

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 G_i 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 G_i-PI3K/Akt-Bcl-2 pathway to protect cells against apoptosis. This may represent an important mechanism underlying the vascular protective effect of DHEA.

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