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(Stroke. 2005;36:1264.)
© 2005 American Heart Association, Inc.

Original Contributions

Neuroprotection by Hypoxic Preconditioning Involves Oxidative Stress-Mediated Expression of Hypoxia-Inducible Factor and Erythropoietin

Jing Liu, MD, PhD; Purnima Narasimhan, PhD; Fengshan Yu, MD Pak H. Chan, PhD

From the Department of Neurosurgery, Department of Neurology and Neurological Sciences, and Program in Neurosciences, Stanford University School of Medicine, Stanford, California.

Correspondence to Pak H. Chan, PhD, Neurosurgical Laboratories, Stanford University, 1201 Welch Rd, MSLS #P314 Stanford, CA 94305-5487. E-mail phchan{at}stanford.edu

Background and Purpose— Hypoxic preconditioning is an endogenous protection against subsequent lethal hypoxia, but the mechanism involved is not understood. Hypoxia is followed by reactive oxygen species (ROS) production and induces hypoxia-inducible factor (HIF) and its downstream factor erythropoietin (Epo), which is associated with neuroprotection. We hypothesized that these endogenous processes may contribute to hypoxic preconditioning.

Methods— We used a mouse neuronal culture model, with 2 hours of hypoxia as preconditioning followed by 15 hours of hypoxic insult, and examined the expression of HIF-1, Epo, and their downstream proteins by Western blotting. Copper/zinc–superoxide dismutase (SOD1) transgenic (Tg) mice were used to detect the effect of ROS. Cell survival and apoptosis were detected by mitogen-activated protein 2 quantification, apoptotic-related DNA fragmentation, and caspase-3 fragmentation. Antisense Epo was used to block endogenously produced Epo.

Results— Hypoxic preconditioning was protective in wild-type (Wt) neurons but not in neurons obtained from SOD1 Tg mice. In Wt neurons, HIF-1 and Epo expression showed a greater increase after hypoxia compared with Tg neurons and reached a higher level with preconditioned hypoxia, followed by pJak2, pStat5, and nuclear factor B (NF-B) expression. Antisense Epo decreased these downstream proteins and the neuroprotection of hypoxic preconditioning.

Conclusions— Hypoxic preconditioning induces ROS, which may downregulate the threshold for production of HIF-1 and Epo expression during subsequent lethal hypoxia, thus exerting neuroprotection through the Jak2–Stat5 and NF-B pathways.

Key Words: superoxide dismutase

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