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This Article Full Text Full Text (PDF) All Versions of this Article: 292/5/H2467    most recent 00649.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zhande, R. Articles by Karsan, A. Search for Related Content PubMed PubMed Citation Articles by Zhande, R. Articles by Karsan, A.

Erythropoietin promotes survival of primary human endothelial cells through PI3K-dependent, NF-B-independent upregulation of Bcl-x_L

Department of Pathology and Laboratory Medicine, University of British Columbia; and Departments of Medical Biophysics and Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3 Canada

Submitted 16 June 2006 ; accepted in final form 17 January 2007

Erythropoietin (EPO) regulates the production of red blood cells primarily by preventing apoptosis of erythroid progenitors. More recently, however, EPO has emerged as a major cytoprotective cytokine in several nonhemopoietic tissues in the setting of stress or injury. The underlying mechanisms of the protective responses of EPO have not been fully defined. Here we show that EPO triggers a phosphatidylinositol 3-kinase-(PI3K)-dependent survival pathway that counteracts endothelial cell death. The protection conferred by PI3K relies on the subsequent induction of Bcl-x_L, a prosurvival member of the Bcl-2 protein family. In addition, EPO counteracts the upregulation of the pro-apoptotic BH3-only protein BIM, which is induced by serum withdrawal. EPO also activates extracellular signal-regulated kinase 1 and 2 (ERK1/2), which are involved in a Bcl-x_L-independent cytoprotective pathway. EPO caused a prolonged activation of nuclear factor (NF)-B, which was blocked by inhibition of PI3K, but not by inhibition of mitogen-activated protein (MAP)/ERK kinase (MEK), suggesting that EPO-activated NF-B requires PI3K activity. However, the activation of the NF-B pathway was not required for the ability of EPO to counteract endothelial apoptosis. Thus EPO promotes survival of endothelial cells through PI3K-dependent Bcl-x_L-induction and BIM regulation, as well as through a separate mechanism involving the ERK pathway.

human umbilical vein endothelial cells; apoptosis; extracellular signal-regulated kinase; pro-apoptotic BH3-only protein; Bcl-2