Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator that mediates changes in gene expression in response to changes in cellular oxygen concentrations. HIF-1 is a heterodimer consisting of an oxygen-regulated HIF-1 alpha subunit and a constitutively expressed HIF-1 beta subunit. In mice, complete HIF-1 alpha deficiency results in embryonic lethality at midgestation because of cardiac and vascular malformations. Analyses of animal and cell culture models as well as human tissue have provided evidence that HIF-1 plays important roles in the pathophysiology of preeclampsia, intrauterine growth retardation, hypoxia-mediated pulmonary hypertension, and cancer. HIF-1 promotes neovascularization in response to myocardial or retinal ischemia by activating transcription of the gene encoding vascular endothelial growth factor. HIF-1 may also mediate the protective response to cerebral ischemia known as late-phase preconditioning.
 ...
PMID:Hypoxia-inducible factor 1: control of oxygen homeostasis in health and disease. 1132 42

Hypoxia inducible factor-1 alpha (HIF-1 alpha) and vascular endothelial growth factor (VEGF) expression were studied in rat cerebral cortex after reversible global cerebral ischemia produced by cardiac arrest and resuscitation. Immunoblot analysis showed a significant induction of HIF-1 alpha protein after 1 hour of recovery from cardiac arrest which remained elevated for at least 12 hours. Upregulation of VEGF mRNA and protein were also observed but this was delayed in comparison to the HIF-1 alpha response. VEGF188 and VEGF164 mRNA levels were increased at 12-48 h of recovery from cardiac arrest but returned to basal expression after 7 days. Changes in VEGF120 mRNA expression did not reach statistical significance. Correspondingly, VEGF protein levels increased by about double at 24 and 48 hours of recovery but returned to basal levels after 7 days. These results suggest that cardiac arrest and resuscitation triggers HIF-1 alpha induction, which might be at least in part responsible for the stimulation of VEGF expression.
 ...
PMID:HIF-1 alpha and VEGF expression after transient global cerebral ischemia. 1456 58

The identification of genes differentially regulated by ischemia will lead to an improved understanding of cell death pathways such as those involved in the neuronal loss observed following a stroke. Furthermore, the characterization of such pathways could facilitate the identification of novel targets for stroke therapy. We have used a novel approach to amplify differential gene expression patterns in a primary neuronal model of stroke by employing a lentiviral vector system to specifically bias the transcriptional activation of hypoxically regulated genes. Overexpression of the hypoxia-induced transcription factor subunits HIF-1 alpha and HIF-2 alpha elevated hypoxia-mediated transcription of many known HIF-regulated genes well above control levels. Furthermore, many potentially novel HIF-regulated genes were discovered that were not previously identified as hypoxically regulated. Most of the novel genes identified were activated by a combination of HIF-2 alpha overexpression and hypoxic insult. These included several genes with particular importance in cell survival pathways and of potential therapeutic value. Hypoxic induction of HIF-2 alpha may therefore be a critical factor in mediating protective responses against ischemic injury. Further investigation of the genes identified in this study may provide increased understanding of the neuronal response to hypoxia and may uncover novel therapeutic targets for the treatment of cerebral ischemia.
 ...
PMID:Identification of potential stroke targets by lentiviral vector mediated overexpression of HIF-1 alpha and HIF-2 alpha in a primary neuronal model of hypoxia. 1474 51

Global cerebral ischemia is an important clinical problem with few effective treatments. The hippocampus, which is important for memory, is especially vulnerable during global ischemia. Brain-specific knockout of hypoxia inducible factor-1 alpha (HIF-1 alpha) has been shown to be protective in focal ischemia in vivo. 2-methoxyestradiol (2ME2) is a natural metabolite of estrogen that is known to inhibit HIF-1 alpha. We tested 2ME2 in a rat model of global cerebral ischemia. Global ischemia was induced with the two-vessel occlusion model (2VO) which entailed hemorrhagic hypotension to a mean arterial pressure of 38-42 mmHg with simultaneous bilateral common carotid artery occlusion for 8 minutes. Sprague-Dawley rats (male, 280-350 g) were randomly assigned to three groups: global ischemia (GI, n=17), global ischemia with 2ME2 treatment (GI + 2ME2, n=17) and sham surgery (sham, n=12). 2ME2 treatment (15 mg/kg in 1% DMSO) was rendered 10 minutes after reperfusion. Rats in the GI and sham groups received similar doses of the DMSO solvent. Rats were killed 24 hours, 72 hours and 7 days after reperfusion. Quantitative CA1 hippocampal cell counts demonstrated significantly lower cell survival in the GI + 2ME2 group compared to either the GI or sham groups, in spite of a statistically significant reduction in HIF-1 alpha by Western blotting analysis of the GI + 2ME2 group. We conclude that 2ME2 worsens outcomes after global ischemia in rats.
 ...
PMID:The effect of 2-methoxyestradiol, a HIF-1 alpha inhibitor, in global cerebral ischemia in rats. 1771 91

In cerebral tissues, due to continuous and high metabolic demand, energy is produced exclusively by mitochondrial oxidative phosphorylation (OXPHOS). Obstruction of blood flow leads to cerebral ischemia, hypoxia and decreased cellular ATP production. The reactive oxygen species (ROS) generated as by-product of OXPHOS alter many intracellular signaling pathways and result in damaged cellular components. Under such hypoxic conditions, a key factor known as hypoxia inducible factor 1 (HIF1) is stabilized and activated and such activation induces expression of a defined set of target genes which are required for cell survival and angiogenesis. Reperfusion that follows such ischemia alters signaling pathways which are involved in cellular fate. Here, we will review the role of ROS, HIF-1 alpha and other signaling network in mitochondrial dysfunction and cell fate determination in ischemia-reperfusion models in the brain. We will also address both current and future therapeutic strategies for clinical significance that are being developed for treatment of cerebral ischemia.
 ...
PMID:Cerebral ischemic stroke: cellular fate and therapeutic opportunities. 3046 65