Role of hypoxia-inducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain

Abstract

Hypoxia‐inducible factor‐1 (HIF‐1) is a heterodimer composed of HIF‐1α and HIF‐1β protein subunits. This transcription factor is essential for the activation of hypoxia‐inducible genes like erythropoietin, some glucose transporters, the glycolytic enzymes, and vascular endothelial growth factor. Because HIF‐1 activation may promote cell survival in hypoxic tissues, we studied the effect of hypoxic preconditioning on HIF‐1 expression in neonatal rat brain. Hypoxic preconditioning (8% O2 for 3 hours), a treatment known to protect the newborn rat brain against hypoxic‐ischemic injury, markedly increased HIF‐1α and HIF‐1β expression. To support the role of HIF‐1 in protective preconditioning, we also studied the effect of two other known HIF‐1 inducers, cobalt chloride (CoCl2) and desferrioxamine (DFX), on HIF‐1 expression and neuroprotection in newborn brain. HIF‐1α and HIF‐1β protein levels were markedly increased after intraperitoneal injection of CoCl2 (60 mg/kg) and moderately increased after intraperitoneal injection of DFX (200 mg/kg) 1 to 3 hours after the injections. Preconditioning with CoCl2 or DFX 24 hours before hypoxia‐ischemia afforded 75 and 56% brain protection, respectively, compared with that in vehicle‐injected littermate controls. Thus, HIF‐1 activation could contribute to protective brain preconditioning, which could be used in high‐risk deliveries and other clinical situations. Ann Neurol 2000;48:285–296

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibition: Robust New Target or Another Big Bust for Stroke Therapeutics?

“…Finally, cobalt chloride had been previously shown to act as a hypoxia mimic and it, like DFO, stabilized HIF and protected neurons from oxidative death. Moreover, in vitro and in vivo studies using DFO or cobalt chloride in several models showed dramatic neuroprotection or reductions in infarct volume by pretreatment with DFO or cobalt chloride 24 hours before stroke onset (Sharp et al, 2004;Gidday et al, 1994;Bergeron et al, 2000;Semenza, 2000;Prass et al, 2002).…”

The experimental study of hypoxia-inducible factor-1α and its target genes in spinal cord injury

“…Furthermore, some reports on the relationship between HIF-1a and the central nervous system (CNS) showed the activation of HIF-1a in the hypoxia-induced ischemic tolerance following brain injury, and revealed that it contributed to protective brain preconditioning. [11][12][13][14] For example, preconditioning with cobalt chloride (CoCl 2 ) or desferrioxamine (DFX), the known HIF-1 inducers, before hypoxia-ischemia, afforded 75 and 56% brain protection, respectively. 12 Even though the spinal cord undergoes ischemia and subsequent hypoxia in acute postinjury phase in SCI, the expression of HIF-1a has not been well documented.…”

“…[11][12][13][14] For example, preconditioning with cobalt chloride (CoCl 2 ) or desferrioxamine (DFX), the known HIF-1 inducers, before hypoxia-ischemia, afforded 75 and 56% brain protection, respectively. 12 Even though the spinal cord undergoes ischemia and subsequent hypoxia in acute postinjury phase in SCI, the expression of HIF-1a has not been well documented. 15 In the present study, a compressive rodent model of SCI was established.…”

Expression of constitutively stable hybrid hypoxia-inducible factor-1α protects cultured rat cardiomyocytes against simulated ischemia-reperfusion injury

“…Whereas HIF-1␤ is constitutively expressed, the stability, DNA binding capability, and transcriptional activity of the HIF-␣ subunit are directly controlled by the intracellular oxygen concentration (9,12,32). Recent studies have demonstrated that protection of rat brain and retinal tissues by prior exposure to an episode of sublethal hypoxia is associated with elevated levels of the HIF-1␣ protein (6,7,14,30). In the neonatal rat brain HIF-1 target genes including vascular endothelial growth factor (VEGF) and Glut-1 have been shown to be upregulated by preconditioning stimulus.…”