Brain-Specific Knock-Out of Hypoxia-Inducible Factor-1α Reduces Rather Than Increases Hypoxic-Ischemic Damage

Helton, Rob; Cui, Jiankun; Ellison, Julie A.; Ames, Chris; Gibson, Claire; Blouw, Barbara; Ouyang, Ling; Dragatsis, Ioannis; Zeitlin, Scott; Johnson, Randall S.; Lipton, Stuart A.; Barlow, Carrolee

doi:10.1523/jneurosci.4555-04.2005

Cited by 227 publications

(188 citation statements)

References 31 publications

Supporting

Mentioning

173

Contrasting

Order By: Relevance

“…The possible differential roles of HIF-1 in different cell types may provide partial explanations for the divergent results from different groups. In our study, as well as the study by Helton et al (Helton et al, 2005), HIF-1α inhibition involved neuronal as well as non-neuronal cell types in the CNS, which may result in an overall pathological role for HIF-1α. Therefore, it is possible that the benefits of blocking HIF-1α across non-neuronal cell types outweigh the potential negative side effects of neuron specific HIF-1α blockade.…”

Section: Discussionsupporting

confidence: 80%

“…Recent reports have suggested that HIF-1α inhibition after cerebral ischemia imparts neuroprotection in adult experimental models (Chang et al, 2007;Chen et al, 2007). A study of brain-specific knockouts of HIF-1α in mice after hypoxic injury suggested that HIF-1α is implicated in brain damage and decreasing the level of HIF-1α could be neuroprotective (Helton et al, 2005). Thus, HIF-1α seems to be capable of playing a dual role by activating both pro-death and anti-apoptotic pathways (Chang et al, 2007;Chen et al, 2007;Baranova et al, 2007;Helton et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…A study of brain-specific knockouts of HIF-1α in mice after hypoxic injury suggested that HIF-1α is implicated in brain damage and decreasing the level of HIF-1α could be neuroprotective (Helton et al, 2005). Thus, HIF-1α seems to be capable of playing a dual role by activating both pro-death and anti-apoptotic pathways (Chang et al, 2007;Chen et al, 2007;Baranova et al, 2007;Helton et al, 2005). Baranova et al have recently shown a biphasic time course for the regulation of HIF-1α activation after cerebral ischemia (Baranova et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

HIF-1α inhibition ameliorates neonatal brain injury in a rat pup hypoxic–ischemic model

Chen

Jadhav

Tang

et al. 2008

Neurobiology of Disease

112

View full text Add to dashboard Cite

Hypoxia-inducible factor-1alpha (HIF-1α) has been considered as a regulator of both prosurvival and prodeath pathways in the nervous system. The present study was designed to elucidate the role of HIF-1α in neonatal hypoxic-ischemic (HI) brain injury. Rice-Vannucci model of neonatal hypoxicischemic brain injury was used in seven-day-old rats, by subjecting unilateral carotid artery ligation followed by 2h of hypoxia (8% O 2 at 37°C). HIF-1α activity was inhibited by 2-methoxyestradiol (2ME2) and enhanced by dimethyloxalylglycine (DMOG). Results showed that 2ME2 exhibited dose-dependent neuroprotection by decreasing infarct volume and reducing brain edema at 48 h post HI. The neuroprotection was lost when 2ME2 was administered 3 h post HI. HIF-1α upregulation by DMOG increased the permeability of the BBB and brain edema compared with HI group. 2ME2 attenuated the increase in HIF-1α and VEGF 24 h after HI. 2ME2 also had a long-term effect of protecting against the loss of brain tissue. The study showed that the early inhibition of HIF-1α acutely after injury provided neuroprotection after neonatal hypoxia-ischemia which was associated with preservation of BBB integrity, attenuation of brain edema, and neuronal death.

show abstract

Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

HIF-1α inhibition ameliorates neonatal brain injury in a rat pup hypoxic–ischemic model

Chen

Jadhav

Tang

et al. 2008

Neurobiology of Disease

112

View full text Add to dashboard Cite

show abstract

“…Hypoxiainducible factor-1a has an essential role in cellular and systemic oxygen homeostasis by regulating the expression of genes important in glycolysis, erythropoiesis, angiogenesis, and catecholamine metabolism (Semenza, 2010). Hypoxia-inducible factor-1a-deficient mice were protected from hypoxia-induced cell death, suggesting that decreasing the level of HIF-1a can be neuroprotective (Helton et al, 2005). Under conditions of low oxygen, HIF-1a accumulation leads to the expression of the fur gene and transcription of the protein, Furin, which activates MMP-14, resulting in the activation of the constitutive enzyme, MMP-2 (Figure 3).…”

Section: Neuroimaging Of the Neurovascular Unitmentioning

confidence: 99%

Neurological Diseases in Relation to the Blood–Brain Barrier

Rosenberg

2012

J Cereb Blood Flow Metab

376

270

View full text Add to dashboard Cite

Disruption of the blood-brain barrier (BBB) has an important part in cellular damage in neurological diseases, including acute and chronic cerebral ischemia, brain trauma, multiple sclerosis, brain tumors, and brain infections. The neurovascular unit (NVU) forms the interface between the blood and brain tissues. During an injury, the cascade of molecular events ends in the final common pathway for BBB disruption by free radicals and proteases, which attack membranes and degrade the tight junction proteins in endothelial cells. Free radicals of oxygen and nitrogen and the proteases, matrix metalloproteinases and cyclooxgyenases, are important in the early and delayed BBB disruption as the neuroinflammatory response progresses. Opening of the BBB occurs in neurodegenerative diseases and contributes to the cognitive changes. In addition to the importance of the NVU in acute injury, angiogenesis contributes to the recovery process. The challenges to treatment of the brain diseases involve not only facilitating drug entry into the brain, but also understanding the timing of the molecular cascades to block the early NVU injury without interfering with recovery. This review will describe the molecular and cellular events associated with NVU disruption and potential strategies directed toward restoring its integrity.

show abstract

“…For example, two groups used the same murine model to invalidate HIF-1␣ expression in neurons (floxed HIF-1 mice crossed with CAM-Cre mice (Cre recombinase under the control of the calcium calmodulindependent kinase promoter)). They observed opposite effects after hypoxia or ischemia: a deleterious or a protective effect of HIF-1␣ expression for neuronal survival (Helton et al, 2005;Baranova et al, 2007). There may be several reasons for this difference in findings.…”

Section: Discussionmentioning

confidence: 99%

Cell-Autonomous and Non-Cell-Autonomous Neuroprotective Functions of RORα in Neurons and Astrocytes during Hypoxia

Jolly¹,

Journiac²,

Naudet³

et al. 2011

J. Neurosci.

View full text Add to dashboard Cite

There is increasing evidence to suggest that the neuronal response to hypoxia is regulated through their interactions with astrocytes. However, the hypoxia-induced molecular mechanisms within astrocytes which influence neuronal death have yet to be characterized. In this study, we investigated the roles of the nuclear receptor ROR␣ (retinoid-related orphan receptor-␣) respectively in neurons and astrocytes during hypoxia using cultures and cocultures of neurons and astrocytes obtained from ROR␣-deficient mice. We found that loss of ROR␣ function in neuronal cultures increases neuronal death after hypoxia, suggesting a cell-autonomous neuroprotective effect of ROR␣. Moreover, wild-type neurons cocultured with ROR␣-deficient astrocytes are characterized by a higher death rate after hypoxia than neurons cocultured with wild-type astrocytes, suggesting that ROR␣ also has a non-cell-autonomous action. By using cocultures of neurons and astrocytes of different genotypes, we showed that this neuroprotective effect of ROR␣ in astrocytes is additive to its effect in neurons, and is mediated in part by cell-to-cell interactions between neurons and astrocytes. We also found that ROR␣ is upregulated by hypoxia in both neurons and astrocytes. Furthermore, our data showed that ROR␣ does not alter oxidative mechanisms during hypoxia but regulates hypoxic inducible factor 1␣ (HIF-1␣) expression, a major regulator of hypoxia sensing, in a cell-specific manner. Indeed, the neuroprotective function of ROR␣ in astrocytes correlates with a downregulation of HIF-1␣ selectively in these cells. Altogether, our results show that ROR␣ is a key molecular player in hypoxia, protecting neurons through its dual action in neurons and astrocytes.

show abstract

Brain-Specific Knock-Out of Hypoxia-Inducible Factor-1α Reduces Rather Than Increases Hypoxic-Ischemic Damage

Cited by 227 publications

References 31 publications

HIF-1α inhibition ameliorates neonatal brain injury in a rat pup hypoxic–ischemic model

HIF-1α inhibition ameliorates neonatal brain injury in a rat pup hypoxic–ischemic model

Neurological Diseases in Relation to the Blood–Brain Barrier

Cell-Autonomous and Non-Cell-Autonomous Neuroprotective Functions of RORα in Neurons and Astrocytes during Hypoxia

Contact Info

Product

Resources

About