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Submitted on October 10, 2006
Accepted on March 16, 2007
i-Protein-Dependent Activation of Phosphatidylinositol 3-Kinase/Akt and Regulation of Anti-apoptotic Bcl-2 expression
The Department of Human Nutrition, Foods and Exercise (D.L., H.S., K.A.R., W.Z.,), and Department of Biomedical Sciences and Pathobiology (Z.J.), Virginia Polytechnic Institute and State University, Blacksburg, VA 24061; and Iowa City VA Medical Center and Division of Endocrinology, Department of Internal Medicine (J.S.D.), Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242
* To whom correspondence should be addressed. E-mail: doliu{at}vt.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 (BAEC) resulted in rapid, and dose-dependent phosphorylation of Akt which was blocked by LY494002, 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 anti-apoptotic 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 (ER)-independent, since these effects were blocked by pertussis toxin but not by the ER inhibitor, ICI182,780, or the aromatase inhibitor, aminoglutethimide. Finally, DHEA enhanced anti-apoptotic Bcl-2 protein expression, its promoter activity and gene transcription due to the activation of the PI3K/Akt pathway. Neutralization of Bcl-2 by antibody transfection significantly decreased the anti-apoptotic effect of DHEA. These findings provide the first evidence that DHEA acts as a survival factor for ECs by triggering the Gi-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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