Gene/Protein Disease Symptom Drug Enzyme Compound
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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) activates transcription of genes encoding proteins that mediate adaptive responses to reduced oxygen availability. The HIF-1beta subunit is constitutively expressed, whereas the HIF-1alpha subunit is subject to ubiquitination and proteasomal degradation, a process that is inhibited under hypoxic conditions. Recent data indicate that HIF-1 plays major roles in the prevention of myocardial and cerebral ischemia and in the pathogenesis of pulmonary hypertension and cancer. Modulation of HIF-1 activity by genetic or pharmacological means could provide a novel therapeutic approach to these common causes of mortality.
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PMID:Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. 1151 94

HIF-1 is composed of HIF-1alpha and HIF-1beta protein subunits. HIF-1 is induced by hypoxia and binds to promoter/enhancer elements and stimulates the transcription of hypoxia-inducible target genes. Because HIF-1 activation might promote cell survival in hypoxic tissues, we studied the effect of stroke on the expression of HIF-1alpha, HIF-1beta and several HIF-1 target genes in adult rat brain. After focal cerebral ischemia, mRNAs encoding HIF-1alpha, glucose transporter-1 and several glycolytic enzymes including lactate dehydrogenase were up-regulated in the areas around the infarction. HIF and its target genes were induced by 7.5 hours after the onset of ischemia and increased further at 19 and 24 hours. Since hypoxia induces HIF in other tissues, systemic hypoxia (6% O2 for 4.5 h) was also shown to increase HIF-1alpha protein expression in the adult rat brain. It is proposed that decreased blood flow to the penumbra decreases the supply of oxygen and that this induces HIF-1 and its target genes. 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% O2/3 hrs), a treatment known to protect the newborn rat brain against hypoxic-ischemic injury, markedly increased HIF-1alpha and HIF-1beta expression. 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-1alpha and HIF-1beta protein levels were markedly increased after i.p. injection of CoCl2 and DFX. Preconditioning with CoCl2 or DFX 24 hours before the stroke decreased infarction by 75% and 56% respectively, compared with vehicle-injected, littermate controls. Thus, HIF-1 activation could contribute to protective brain preconditioning.
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PMID:Hypoxia-inducible factor in brain. 1195 Jan 44

Hypoxia-inducible factor-1 (HIF-1), a transcription factor composed of HIF-1alpha and HIF-1beta protein subunits, has been implicated in cellular protection and cell death in cerebral ischemia. The extent to which HIF-1 plays a role in brain pathology during intracerebral hemorrhage (ICH) is unknown. This study determined whether HIF-1alpha is upregulated at different time points in a rat model of ICH and the role of thrombin and red blood cell lysis in upregulation. Recently, thrombin has been implicated as a nonhypoxic regulator of HIF-1alpha in cultured smooth-muscle cells. Male Sprague-Dawley rats received intracerebral infusions of saline, autologous whole blood, blood plus hirudin, thrombin, thrombin plus hirudin, or lysed erythrocytes. Rats were killed at different time points for Western blot analysis, immunohistochemistry, immunofluorescent double staining, and reverse transcription polymerase chain reaction measurements of HIF-1alpha. HIF-1alpha protein levels increased without changing HIF-1alpha messenger RNA levels after intracerebral infusions of blood, thrombin, and lysed erythrocytes. HIF-1alpha positive cells, which proved to be neurons, were found in the brain after ICH. Hirudin, a specific thrombin inhibitor, reduced HIF-1alpha upregulation in response to both thrombin and blood. This study demonstrates that perihematomal HIF-1alpha protein is upregulated after ICH. This phenomenon is an early response of brain parenchyma to the clot. Thrombin and erythrocyte lysate are involved in HIF-1alpha upregulation through reducing HIF-1alpha degradation.
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PMID:Hypoxia-inducible factor-1alpha accumulation in the brain after experimental intracerebral hemorrhage. 1204 67

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates the adaptive response to hypoxia in mammalian cells. It consists of a regulatory subunit HIF-1alpha, which accumulates under hypoxic conditions, and a constitutively expressed subunit HIF-1beta. In this study we analyzed HIF-1alpha expression in the rat cerebral cortex after transient global ischemia induced by cardiac arrest and resuscitation. Our results showed that HIF-1alpha accumulates as early as 1 hr of recovery and persists for at least 7 d. In addition, the expression of HIF-1 target genes, erythropoietin and Glut-1, were induced at 12 hr to 7d of recovery. A logical explanation for HIF-1alpha accumulation might be that the brain remained hypoxic for prolonged periods after resuscitation. By using the hypoxic marker 2-(2-nitroimidazole-1[H]-y1)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide (EF5), we showed that the brain is hypoxic during the first hours of recovery from cardiac arrest, but the tissue is no longer hypoxic at 2 d. Thus, the initial ischemic episode must have activated other nonhypoxic mechanisms that maintain prolonged HIF-1alpha accumulation. One such mechanism might be initiated by insulin-like growth factor-1 (IGF-1). Our results showed that IGF-1 expression was upregulated after cardiac arrest and resuscitation. In addition, we showed that IGF-1 was able to induce HIF-1alpha in pheochromocytoma cells and cultured neurons as well as in the brain of rats that received intracerebroventricular and systemic IGF-1 infusion. Moreover, infusion of a selective IGF-1 receptor antagonist abrogates HIF-1alpha accumulation after cardiac arrest and resuscitation. Our study suggest that activation of HIF-1 might be part of the mechanism by which IGF-1 promotes cell survival after cerebral ischemia.
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PMID:Activation of hypoxia-inducible factor-1 in the rat cerebral cortex after transient global ischemia: potential role of insulin-like growth factor-1. 1238 99