Harnessing hypoxic adaptation to prevent, treat, and repair stroke

Ratan, Rajiv R.; Siddiq, Ambreena; Smirnova, Natalia; Karpisheva, Ksenia; Haskew-Layton, Renée E.; McConoughey, Stephen J.; Langley, Brett; Estévez, Álvaro G.; Huerta, Patricio T.; Volpe, Bruce T.; Roy, Sashwati; Sen, Chandan K.; Gazaryan, I. G.; Cho, Sunghee; Fink, Matthew E.; LaManna, Joseph Charles

doi:10.1007/s00109-007-0283-1

Cited by 74 publications

(62 citation statements)

References 58 publications

(50 reference statements)

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“…To date most research has concentrated on the cellular adaptation that requires long-tem adaptive changes including gene expression changes, which involve transcription factors [48].…”

Section: Tnf-α and Hypoxia In The Cnsmentioning

confidence: 99%

Targeting tumour necrosis factor-α in hypoxia and synaptic signalling

O’Connor

2013

Ir J Med Sci

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Tumor necrosis factor (TNF)-α is a proinflammatory cytokine, which is synthesised and released in the brain by astrocytes, microglia and neurons in response to numerous internal and external stimuli. It is involved in many physiological and pathophysiological processes such as gene transcription, cell proliferation, apoptosis, synaptic signalling and neuroprotection. The complex actions of TNF-α in the brain are under intense investigation. TNF-α has the ability to induce selective necrosis of some cells whilst sparing others and this has led researchers to discover multiple activated signalling cascades. In many human diseases including acute stroke and inflammation and those involving hypoxia, levels of TNF-α are increased throughout different brain regions. TNF-α signalling may also have several positive and negative effects on neuronal function including glutamatergic synaptic transmission and plasticity. Exogenous TNF-α may also exacerbate the neuronal response to hypoxia. This review will summarise the actions of TNF-α in the central nervous system on synaptic signalling and its effects during hypoxia.

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“…To date most research has concentrated on the cellular adaptation that requires long-tem adaptive changes including gene expression changes, which involve transcription factors [48].…”

Section: Tnf-α and Hypoxia In The Cnsmentioning

confidence: 99%

Targeting tumour necrosis factor-α in hypoxia and synaptic signalling

O’Connor

2013

Ir J Med Sci

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“…It is thought that the consequences of inadequate tissue oxygenation, such as seen in anemia, stroke, and ischemic cardiovascular diseases, might be mitigated by increased levels of HIF (9), and therefore, pharmacologic inhibitors of EGLN prolyl hydroxylase activity might have therapeutic benefits. Preclinical studies have shown that prolyl hydroxylase inhibitors are useful for treatment of anemia (10) and may protect against ischemic renal disease (11), myocardial infarction (12), stroke (13), and whole body hypoxia (14).…”

mentioning

confidence: 99%

Prolyl Hydroxylase EGLN3 Regulates Skeletal Myoblast Differentiation through an NF-κB-dependent Pathway

Taubman

2010

Journal of Biological Chemistry

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The egg-laying abnormal-9 (EGLN) prolyl hydroxylases have been shown to regulate the stability and thereby the activity of the ␣ subunits of hypoxia-inducible factor (HIF) through its ability to catalyze their hydroxylation. We have previously shown that EGLN3 promotes differentiation of C2C12 skeletal myoblasts. However, the mechanism underlying this effect remains to be fully elucidated. Here, we report that exposure of C2C12 cells to dimethyl oxalylglycine (DMOG), desferrioxamine, and hypoxia, all inhibitors of prolyl hydroxylase activity, led to repression of C2C12 myogenic differentiation. Inactivation of HIF by expression of a HIF dominant-negative mutant or deletion of HIF-1␣ by RNA interference did not affect the inhibitory effect of DMOG, suggesting that the effect of DMOG is HIFindependent. Pharmacologic inactivation of EGLN3 hydroxylase resulted in activation of the canonical NF-B pathway. The inhibitory effect of DMOG on myogenic differentiation was markedly impaired in C2C12 cells expressing a dominant-negative mutant of IB␣. Exogenous expression of wild-type EGLN3, but not its catalytically inactive mutant, significantly inhibited NF-B activation induced by overexpressed TRAF2 or IB kinase 2. In contrast, deletion of EGLN3 by small interfering RNAs led to activation of NF-B. These data suggest that EGLN3 is a negative regulator of NF-B, and its prolyl hydroxylase activity is required for this effect. Furthermore, wild-type EGLN3, but not its catalytically inactive mutant, potentiated myogenic differentiation. This study demonstrates a novel role for EGLN3 in the regulation of NF-B and suggests that it is involved in mediating myogenic differentiation, which is HIF-independent. EGLN2 prolyl hydroxylases belong to the superfamily of oxygenases that require O 2 , 2-oxoglutarate, and Fe 2ϩ for their enzymatic activity (1-5). There are three mammalian EGLN prolyl hydroxylases, termed EGLN1, -2, and -3 (6, 7). Although their biologic functions remain to be fully defined, the EGLN prolyl hydroxylases have been shown to regulate the transcription factor hypoxia-inducible factor (HIF)-␣ (2, 3). Inhibition of EGLN prolyl hydroxylase activity with dimethyl oxalylglycine (DMOG), an analog of 2-oxoglutarate, desferrioxamine (DFX), an iron chelator, or hypoxia stabilizes HIF proteins (2,3,8). It is thought that the consequences of inadequate tissue oxygenation, such as seen in anemia, stroke, and ischemic cardiovascular diseases, might be mitigated by increased levels of HIF (9), and therefore, pharmacologic inhibitors of EGLN prolyl hydroxylase activity might have therapeutic benefits. Preclinical studies have shown that prolyl hydroxylase inhibitors are useful for treatment of anemia (10) and may protect against ischemic renal disease (11), myocardial infarction (12), stroke (13), and whole body hypoxia (14).We previously reported that EGLN3 is up-regulated during C2C12 myogenic differentiation and promotes skeletal muscle differentiation, in part by binding to and enhancing myogenin protein stability (15). Sk...

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“…Recent studies indicate that Epo, vascular endothelial growth factor and SDF-1 are transcriptionally regulated by hypoxia via the transcriptional activator hypoxia-inducible factor 1. 6 These findings suggest that neurogenesis, angiogenesis and chemotaxis of new born neurons into the injury site can be potentially regulated by a drug that stabilized hypoxia-inducible factor 1. Indeed, studies from a number of groups have identified small molecule activators of the hypoxia-inducible factor pathway that are ripe for testing in this context.…”

Section: Giving the Brain A Push: Epo Sdf-1 Angiogenesis And Beyondmentioning

confidence: 99%

“…Indeed, studies from a number of groups have identified small molecule activators of the hypoxia-inducible factor pathway that are ripe for testing in this context. 6 Some of these drugs are already in phase II human clinical trials for other diseases and could be tested in preclinical recovery studies within the year.…”

Section: Giving the Brain A Push: Epo Sdf-1 Angiogenesis And Beyondmentioning

confidence: 99%