Neuron-Specific Inactivation of the Hypoxia Inducible Factor 1  Increases Brain Injury in a Mouse Model of Transient Focal Cerebral Ischemia

Abstract

In the present study, we show a biphasic activation of hypoxia inducible factor 1␣ (HIF-1) after stroke that lasts for up to 10 d, suggesting the involvement of the HIF pathway in several aspects of the pathophysiology of cerebral ischemia. We provide evidence that HIF-1-mediated responses have an overall beneficial role in the ischemic brain as indicated by increased tissue damage and reduced survival rate of mice with neuron-specific knockdown of HIF-1␣ that were subjected to transient focal cerebral ischemia. In addition, we demonstrated that drugs known to activate HIF-1 in cultured cells as well as in vivo had neuroprotective properties in this model of cerebral ischemia. This protective effect was significantly attenuated but not completely abolished in neuron-specific HIF-1␣-deficient mice, suggesting that alternative mechanisms of neuroprotection are also implicated. Last, our study showed that hypoxia-induced tolerance to ischemia was preserved in neuron-specific HIF-1␣-deficient mice, indicating that the neuroprotective effects of hypoxic preconditioning do not depend on neuronal HIF-1 activation.

Targeting Astrocytes for Stroke Therapy

“…27 When ischemia was applied for a longer time frame (90 minutes), however, the infarct damage was maximal within 24 hours after stroke. 27 More typically, a delayed increase in stroke volume is much more subtle or absent in rodent models 13,28,29 ; however, a notable increase in infarct growth may be observed when neuroprotective mechanisms are impaired in the brain, an illustration of the tenuous nature of cell viability in the penumbra. 28,29 Factors such as the presence of edema, peri-infarct depolarizations, 30 -32 inflammatory changes, [33][34][35] or the amount of collateral blood flow likely determine the fate of the penumbra.…”

“…In addition, expression and release of neuroprotective or harmful substances in response to ischemia are also likely determinants of cell death. 13,29,35 Given that astrocytes modulate blood flow, contribute to water homeostasis, participate in inflammatory responses, maintain ion homeostasis, and release a number of substances that may be either neuroprotective or harmful, they undoubtedly contribute to determining the viability of this vulnerable tissue.…”

“…Loss of activity of the transcription factor hypoxia-inducible factor-1 (HIF-1) specifically in neurons enhances infarct growth 24 -96 hours after stroke onset. 29 HIF-1 is expressed at low levels when oxygen availability is not limited, but its protein abundance is markedly induced during hypoxia. Once stabilized, HIF-1 translocates to the nucleus and induces a large number of targets that increase adaptive responses, such as glycolytic enzymes, neuroprotectants (erythropoietin [EPO] and adrenomedullin), and factors that encourage angiogenesis (vascular endothelial growth factor [VEGF]).…”

“…Once stabilized, HIF-1 translocates to the nucleus and induces a large number of targets that increase adaptive responses, such as glycolytic enzymes, neuroprotectants (erythropoietin [EPO] and adrenomedullin), and factors that encourage angiogenesis (vascular endothelial growth factor [VEGF]). 29,38 Thus, at least in neurons, HIF-1 has an adaptive function that impedes growth of stroke volume during this delayed time frame. In neuronastrocyte cocultures, however, HIF-1 activity in astrocytes has the opposite effect on neuronal viability.…”

Alternative Approaches to Modeling Hereditary Dystonias

“…Expression can be further limited to specific cells in a given region by combining lentivirus and cre-lox systems or by altering the promoter of the shRNA [72,73]. For example, by injecting a virus with shRNA containing a premature stop codon that is floxed into Cre-CaMKIIα mice, a neuron specific knockdown can be achieved [74].…”