Hypoxic Preconditioning Induces Changes in HIF-1 Target Genes in Neonatal Rat Brain

Abstract

Hypoxic preconditioning induces tolerance to hypoxic-ischemic injury in neonatal rat brain and is associated with changes in gene expression. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that is strongly induced by hypoxia or the hypoxia-mimetic compound cobalt chloride (CoCl(2)). Hypoxia-inducible factor-1 modulates the expression of several target genes including the glycolytic enzymes, glucose transporter-1 (GLUT-1), and erythropoietin. Recently, HIF-1 expression was shown to increase after hypoxic and CoCl(2) preconditioning in newborn rat brain. To study the involvement of HIF-1 target genes in neonatal hypoxia-induced ischemic tolerance, the authors examined the brains of newborn rats after exposure to hypoxia (8% O(2) for 3 hours) or injection of CoCl(2) (60 mg/kg). Preconditioning with hypoxia or CoCl(2) 24 hours before hypoxia-ischemia afforded a 96% and 76% brain protection, respectively, compared with littermate control animals. Hypoxic preconditioning increased the expression of GLUT-1 mRNA and protein, and of aldolase, phosphofructokinase, and lactate dehydrogenase proteins but not mRNA. This suggests that the modulation of glucose transport and glycolysis by hypoxia may contribute to the development of hypoxia-induced tolerance. In contrast, preconditioning with CoCl(2) did not produce any change in HIF-1 target gene expression suggesting that different molecular mechanisms may be involved in the induction of tolerance by hypoxia and CoCl(2) in newborn brain.

Loss of c/EBP-β activity promotes the adaptive to apoptotic switch in hypoxic cortical neurons

“…However, evidence suggest that cell-autonomous delayed apoptotic signaling plays a critical role in determining the ultimate burden of neuron loss after injury (Abe et al, 1995;Schwamm et al, 1998). Hypoxia is a potent stimulus for de novo gene expression, and sub-lethal hypoxic stress can enhance cell survival through the regulated expression of factors such as erythropoietin and vascular endothelial growth factor (Dirnagl et al, 2003;Jones and Bergeron, 2001). This process, also referred to as ischemic preconditioning, is supported in part by the activation of the hypoxia-inducible factor (HIF-1α) and an array of immediate early transcription factors with diverse biological functions including c-Jun and Egr-1/Krox-24 (Collaco-Moraes et al, 1994;Herdegen and Leah, 1998;Hsu et al, 1993).…”

Brain Genomic Response following Hypoxia and Re-oxygenation in the Neonatal Rat

“…This phenomenon is called tolerance. Ischemic tolerance can be achieved in brain by several preconditioning sublethal stresses such as hypoxia (1-3), ischemia itself (4), hypothermia (5), hyperthermia (6), hyperbaric oxygenation (7), metabolic inhibitors (8), spreading depression (9), as well as cytokines (10, 11).As hypoxic preconditioning is non-invasive and reproducible, this model has been used to study the mechanisms protecting the brain against hypoxia-ischemia particularly in newborn rats (3,(12)(13)(14). In addition, hypoxic preconditioning also induces tolerance against focal transient (15) and permanent (16) cerebral ischemia in adult mice.…”

Modulators of KATP channels in the prevention of oxidative stress and antioxidant capacity improvement in the rat heart with different resistance to hypoxia upon cobalt treatment

“…protects the brain against ischaemic injury, but the mechanisms were found to be different in both cases. These authors reported that hypoxic preconditioning is connected with the modulation of glucose transport and glycolysis by hypoxia and may contribute to the development of hypoxia-induced tolerance (12). In contrast, preconditioning with cobalt chloride did not produce any change in HIF-1 target gene expression.…”

“…Jones and Bergeron (12) reported that prior exposure of newborn rats to 8% hypoxia or CoCl2 (60 mg/kg b.w.) protects the brain against ischaemic injury, but the mechanisms were found to be different in both cases.…”

“…Cobalt chloride is a well-established hypoxia mimetic and inducer of hypoxia-like responses. It can cause gene modulation at the hypoxia-inducible factor pathway to stimulate EPO transcription and increase its levels in blood (12). Low (therapeutic) doses of cobalt chloride may enhance oxygen carrying capacity.…”