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Oxygen Sensing: Life and Death of a Cell

Hypoxic preconditioning protects human brain endothelium from ischemic apoptosis by Akt-dependent survivin activation

Departments of ¹Neurosurgery, ²Anatomy and Neurobiology, and ³Cell Biology and Physiology, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, Missouri

Submitted 6 October 2006 ; accepted in final form 25 February 2007

Preconditioning-induced ischemic tolerance is well documented in the brain, but cell-specific responses and mechanisms require further elucidation. The aim of this study was to develop an in vitro model of ischemic tolerance in human brain microvascular endothelial cells (HBMECs) and to examine the roles of phosphatidylinositol 3-kinase (PI3-kinase)/Akt and the inhibitor-of- apoptosis protein, survivin, in the ability of hypoxic preconditioning (HP) to protect endothelium from apoptotic cell death. Cultured HBMECs were subjected to HP, followed 16 h later by complete oxygen and glucose deprivation (OGD) for 8 h; cell viability was quantified at 20 h of reoxygenation (RO) by the 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide assay. HBMECs were examined at various times after HP or OGD/RO using immunoblotting and confocal laser scanning immunofluorescence microscopy for appearance of apoptotic markers and expression of phosphorylated (p)-Akt and p-survivin. Causal evidence for the participation of the PI3-kinase/Akt pathway in HP-induced protection and p-survivin upregulation was assessed by the PI3-kinase inhibitor LY-294002. HP significantly reduced OGD/RO-induced injury by 50% and also significantly reduced the OGD-induced translocation of apoptosis-inducing factor (AIF) from mitochondria to nucleus and the concomitant cleavage of poly(ADP-ribose) polymerase-1 (PARP-1). PI3-kinase inhibition blocked HP-induced increases in Akt phosphorylation, reversed the effects of HP on OGD-induced AIF translocation and PARP-1 cleavage, blocked HP-induced survivin phosphorylation, and ultimately attenuated HP-induced protection of HBMECs from OGD. Thus HP promotes an antiapoptotic phenotype in HBMECs, in part by activating survivin via the PI3-kinase/Akt pathway. Survivin and other phosphorylation products of p-Akt may be therapeutic targets to protect cerebrovascular endothelium from apoptotic injury following cerebral ischemia.

cell survival; phosphatidylinositol 3-kinase; stroke

This article has been cited by other articles:

				B. K. Wacker, T. S. Park, and J. M. Gidday Hypoxic Preconditioning-Induced Cerebral Ischemic Tolerance: Role of Microvascular Sphingosine Kinase 2 Stroke, October 1, 2009; 40(10): 3342 - 3348. [Abstract] [Full Text] [PDF]

				A. Bellis, D. Castaldo, V. Trimarco, M. G. Monti, P. Chivasso, J. Sadoshima, B. Trimarco, and C. Morisco Cross-Talk Between PKA and Akt Protects Endothelial Cells From Apoptosis in the Late Ischemic Preconditioning Arterioscler Thromb Vasc Biol, August 1, 2009; 29(8): 1207 - 1212. [Abstract] [Full Text] [PDF]

				H.-T. Lee, Y.-C. Chang, Y.-F. Tu, and C.-C. Huang VEGF-A/VEGFR-2 Signaling Leading to cAMP Response Element-Binding Protein Phosphorylation Is a Shared Pathway Underlying the Protective Effect of Preconditioning on Neurons and Endothelial Cells J. Neurosci., April 8, 2009; 29(14): 4356 - 4368. [Abstract] [Full Text] [PDF]

				W. J. Pearce Cerebrovascular effects of ischemic preconditioning: endothelial survivin joins the fray Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2559 - H2560. [Full Text] [PDF]