Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of the receptor for advanced glycation endproducts (RAGE) by its multiple ligands can trigger diverse signaling pathways with injurious or pro-survival consequences. In this study, we show that Rage mRNA and protein levels were stimulated in the mouse brain after experimental stroke and systemic hypoxia. In both cases, RAGE expression was primarily associated with neurons. Activation of RAGE-dependent pathway(s) post-ischemia appears to have a neuroprotective role because mice genetically deficient for RAGE exhibited increased infarct size 24 h after injury. Up-regulation of RAGE expression was also observed in primary neurons subjected to hypoxia or oxygen-glucose deprivation, an in vitro model of ischemia. Treatment of neurons with low concentrations of S100B decreased neuronal death after oxygen-glucose deprivation, and this effect was abolished by a neutralizing antibody against RAGE. Conversely, high concentrations of exogenous S100B had a cytotoxic effect that seems to be RAGE-independent. As an important novel finding, we demonstrate that hypoxic stimulation of RAGE expression is mediated by the transcription factor hypoxia-inducible factor-1. This conclusion is supported by the finding that HIF-1alpha down-regulation by Cre-mediated excision drastically decreased RAGE induction by hypoxia or desferrioxamine. In addition, we showed that the mouse RAGE promoter region contains at least one functional HIF-1 binding site, located upstream of the proposed transcription start site. A luciferase reporter construct containing this RAGE promoter fragment was activated by hypoxia, and mutation at the potential HIF-1 binding site decreased hypoxia-dependent promoter activation. Specific binding of HIF-1 to this putative HRE in hypoxic cells was detected by chromatin immunoprecipitation assay.
 ...
PMID:Hypoxia-inducible factor-1 mediates neuronal expression of the receptor for advanced glycation end products following hypoxia/ischemia. 1794 94

HIF-1alpha is the inducible subunit of the dimeric transcription factor HIF-1 (Hypoxia Inducible Factor 1). It is induced by hypoxia and hypoxia-mimetics in most cell types, as well as non-hypoxic signals such as growth factors, cytokines and oncogenes, often in a cell specific manner. HIF-1 is present in virtually all cells of higher eukaryotes and its function is of great biomedical relevance since it is highly involved in development, tumor progression and tissue ischemia. Intracellular signaling to HIF-1alpha, as well as its further action, involves its participation in numerous protein complexes. Using the yeast two-hybrid system we have identified MgcRacGAP (male germ cell Rac GTPase Activating Protein) as a HIF-1alpha interacting protein. The MgcRacGAP protein is a regulator of Rho proteins, which are principally involved in cytoskeletal organization. We have verified specific binding of HIF-1alpha and MgcRacGAP in vitro and in vivo in mammalian cells. We have additionally shown that MgcRacGAP overexpression inhibits HIF-1alpha transcriptional activity, without lowering HIF-1alpha protein levels, or altering its subcellular localization. Moreover, this inhibition is dependent on the MgcRacGAP domain that interacts with HIF-1alpha. In conclusion, our findings demonstrate that HIF-1alpha function is negatively affected by its interaction with MgcRacGAP.
 ...
PMID:MgcRacGAP interacts with HIF-1alpha and regulates its transcriptional activity. 1798 82

The purpose of this study was to monitor hypoxia in an orthotopic liver tumor model using a hypoxia-sensitive reporter imaging system and to image enhanced gene expression after clamping the hepatic artery. C6 and RH7777 Morris hepatoma cells were transduced with a triple reporter gene (HSV1-tk/green fluorescent protein/firefly luciferase-triple fusion), placed under the control of a HIF-1-inducible hypoxia responsive element (HRE). The cells showed inducible luciferase activity and green fluorescent protein expression in vitro. Isolated reporter-transduced Morris hepatoma cells were used to produce tumors in livers of nude rats, and the effect of hepatic artery clamping was evaluated. Tumor hypoxia was shown by immunofluorescence microscopy with the hypoxia marker EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl acetamide)] and the fluorescent perfusion marker Hoechst 33342, and by pO(2) electrode measurements. For tumor hypoxia imaging with the HRE-responsive reporter, both luciferase bioluminescence and [(18)F]2'-fluoro-2'-deoxyarabinofuranosyl-5-ethyluracil positron emission tomography was done, and the presence of hypoxia in Morris hepatoma tumors were successfully imaged by both techniques. Transient clamping of the hepatic artery caused cessation of tumor perfusion and severe hypoxia in liver tumors, but not in adjacent liver tissue. These results show that the orthotopic reporter-transduced RH7777 Morris hepatomas are natively hypoxic and poorly perfused in this animal model, and that the magnitude of hypoxia can be monitored using a HRE-responsive reporter system for both bioluminescence and positron emission tomography imaging. However, the severity of tumor ischemia after permanent ligation of the hepatic artery limits our ability to image severe hypoxia in this animal model.
 ...
PMID:Imaging of hypoxia-driven gene expression in an orthotopic liver tumor model. 1798 17

Myocardial ischemia, the most common cause of cardiac hypoxia in clinical medicine, occurs when oxygen delivery cannot meet myocardial metabolic requirements in the heart. This deficiency can result from either a reduced supply of oxygen (decreased coronary bloodflow) or an increased myocardial demand for oxygen (increased wall stress or afterload). Patients with stable coronary artery disease as well as patients experiencing acute myocardial infarction can experience episodes of severe ischemia. Although hypoxia is an obligatory component, it is not the sole environmental stress experienced by the ischemic heart. Reperfusion after ischemia is associated with increased oxidative stress as the heart reverts to aerobic respiration and thereby generates toxic levels of reactive oxygen species (ROS). During mild ischemia, mitochondrial function is partially compromised and substrate preferences adapt to sustain adequate ATP generation. With severe ischemia, mitochondrial function is markedly compromised and anaerobic metabolism must provide energy no matter what the cost in generation of toxic ROS adducts. Ischemia produces a variety of environmental stresses that impair cardiovascular function. As a result, multiple signaling pathways are activated in mammalian cells during ischemia/reperfusion injury in an attempt to minimize cellular injury and maintain cardiac output. Amongst the transcriptional regulators activated are members of the hypoxia inducible factor (HIF) transcription factor family. HIF factors regulate a variety of genes that affect a myriad of cellular processes including metabolism, angiogenesis, cell survival, and oxygen delivery, all of which are important in the heart. In this review, we will focus on the metabolic and angiogenic aspects of HIF biology as they relate to the heart during ischemia. We will review the metabolic requirements of the heart under normal as well as hypoxic conditions, the effects of preconditioning and its regulation as it pertains to HIF biology, the apparent roles of HIF-1 and HIF-2 in intermediary metabolism, and translational applications of HIF-1 and HIF-2 biology to cardiac angiogenesis. Increased understanding of the role of HIFs in cardiac ischemia will ultimately influence clinical cardiovascular practice.
 ...
PMID:Keeping the engine primed: HIF factors as key regulators of cardiac metabolism and angiogenesis during ischemia. 1802 17

Hypoxia-Inducible Factor (HIF)-1 is a dimeric protein complex that plays an integral role in the body's response to low oxygen concentrations, or hypoxia. HIF-1 is among the primary genes involved in the homeostatic process, which can increase vascularization in hypoxic areas such as localized ischemia and tumors. It is a transcription factor for dozens of target genes; HIF-1 is also essential for immunological responses and is a crucial physiological regulator of homeostasis, vascularization, and anaerobic metabolism. Furthermore, HIF-1 is increasingly studied because of its perceived therapeutic potential. As it causes angiogenesis, enhancement of this gene within ischemic patients could promote the vessel proliferation needed for oxygenation. In contrast, as HIF-1 allows for survival and proliferation of cancerous cells due to its angiogenic properties, inhibition potentially could prevent the spread of cancer. With a growing understanding of the HIF-1 pathway, the inhibition and stimulation of its transcriptional activity via small molecules is now an attractive goal. Gene therapy to achieve both vessel proliferation and tumor regression has been demonstrated in animal studies but requires significant improvement and modification before becoming commercially available. This review focuses on the potential of the HIF-1 pathway in therapeutic intervention for the treatment of diseases such as cancer and ischemia.
 ...
PMID:Hypoxia-Inducible Factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia. 1816 Sep 90

Hypoxia inducible factor-1alpha (HIF-1alpha) is a key regulator of oxygen homeostasis, because it is responsible for the regulation of genes involved in glycolysis, erythropoiesis, angiogenesis, and apoptosis. In the CNS, HIF-1alpha is stabilized by insults associated with hypoxia and ischemia. Because its many target genes mediate both adaptive and pathological processes, the role of HIF-1alpha in neuronal survival is debated. Although neuronal HIF-1alpha function has been the topic of several studies, the role of HIF-1alpha function in astrocytes has received much less attention. To characterize the role of HIF-1alpha in neurons and astrocytes, we induced loss of HIF-1alpha function specifically in neurons, astrocytes, or both cell types in neuron/astrocyte cocultures exposed to hypoxia. Although loss of HIF-1alpha function in neurons reduced neuronal viability during hypoxia, selective loss of HIF-1 function in astrocytes markedly protected neurons from hypoxic-induced neuronal death. Although the pathological processes induced by HIF-1alpha in astrocytes remain to be defined, induction of inducible nitric oxide synthase likely contributes to the pathological process. This study delineates, for the first time, a cell type-specific action for HIF-1alpha within astrocytes and neurons.
 ...
PMID:The good, the bad, and the cell type-specific roles of hypoxia inducible factor-1 alpha in neurons and astrocytes. 1828 15

The mechanisms of tolerance to subsequent episodes of ischemia induced by cortical spreading depression (CSD) are not clear. The effects of CSD on the expression of inducible nitric oxide synthase (iNOS), hypoxia inducible factor-1alpha (HIF-1alpha), and lactate dehydrogenase-A (LDH-A) were evaluated in the present experiment. Unilateral CSD was induced in Sprague-Dawley rats by application of KCl on the right cortex and the mRNA levels of iNOS, HIF-1alpha, and LDH-A were evaluated at 15 min, 2 h, 4 h, 6 h or 24 h after CSD. RT-PCR analysis showed: 1) an increase of iNOS mRNA at 15 min, 2 h, 4 h; 2) an increase of HIF-1alpha mRNA at 6 h; 3) an increase of LDH-A mRNA at 4 h. In situ hybridization with specific digoxigenin-labeled oligonucleotides revealed that the mRNA levels were increased at 15 min-2 h for iNOS, 2-4 h for LDH-A and 6 h for HIF-1 after CSD. Immunohistochemistry analysis revealed that levels of iNOS and HIF-1alpha were increased, respectively, at 2 h and 6 h after CSD. These data suggest that CSD promotes the expression of iNOS, HIF-1alpha, and LDH-A in nervous cells giving a neuroprotective effect.
 ...
PMID:Cortical spreading depression induces the expression of iNOS, HIF-1alpha, and LDH-A. 1835 26

HIF-1 is believed to play a critical role in hypoxia/ischemia (H/I) preconditioning protection in neonatal brain. Recently, it has been shown that hydrogen peroxide (H(2)O(2)) may contribute to H/I preconditioning in rat primary neurons. We hypothesize that H(2)O(2) produced during H/I preconditioning may increase HIF-1alpha protein expression and contribute to H/I preconditioning protection in the immature brain. To test this hypothesis, we used 6-8 days in vitro (DIV) primary cortical neurons from embryonic day 16 CD1 mouse brains and preconditioned them with 10 min of oxygen and glucose deprivation (OGD) or exogenous H(2)O(2) at doses from 5 to 50 microM. Both OGD and low dose H(2)O(2) (15 microM) preconditioning provided neuronal protection 24 h later against a 2 h OGD insult. Cell survival was 34.9+/-1.8% and 35.8+/-3.8% with OGD and H(2)O(2) preconditioning respectively vs. 20.0+/-0.4% without preconditioning (P<0.01). After OGD preconditioning, HIF-1alpha protein increased at 4 h and peaked at 8h, then declined at 18 h and increased again to reach another peak at 32 h. HIF-1alpha protein following H(2)O(2) preconditioning increased at 8h and peaked at 32 h. For both preconditioning paradigms, HIF-1alpha expression level declined to baseline at 72 h. Our results suggest that low levels of H(2)O(2) may up-regulate HIF-1alpha protein and thereby mediate H/I preconditioning protection.
 ...
PMID:Exogenous low dose hydrogen peroxide increases hypoxia-inducible factor-1alpha protein expression and induces preconditioning protection against ischemia in primary cortical neurons. 1859 36

Hypoxia can activate the endothelium toward a pro-inflammatory phenotype and enhance leukocyte adhesion. This process is involved in pathological conditions such as vascular remodeling or ischemia-reperfusion injury. This study was aimed to obtain a global picture of the response of the endothelial cells to hypoxia with respect to inflammatory genes. To this purpose, we used a low density DNA microarray specifically designed to quantitate the expression of genes involved in the inflammatory pathways and a customized real-time PCR array. The expression of several pro-inflammatory genes known to be NF-kB target genes was decreased after the incubation of endothelial cells under hypoxia. In parallel, a decrease in the DNA binding activity of this transcription factor was observed. On the other hand, HIF-1 DNA binding activity was increased as well as the expression of several genes known to be regulated by this factor. Among them are several pro-inflammatory genes whose overexpression could account for the increase in leukocyte adhesion to the hypoxic endothelial cells. We concluded that hypoxia does not shift the endothelial cell phenotype to a more pro-inflammatory one probably because of a decrease in the expression of several cytokines. On the other hand, a clear response to hypoxia was observed with HIF-1 probably playing an important role in this process.
 ...
PMID:Hypoxia regulates inflammatory gene expression in endothelial cells. 1910 40

Ischemia exists in many diseased tissues, including arthritic joints, atherosclerotic plaques, and malignant tumors. Macrophages accumulate in these sites and up-regulate hypoxia-inducible transcription factors (HIFs) 1 and 2 in response to the hypoxia present. Here we show that the gene expression profile in primary human and murine macrophages changes markedly when they are exposed to hypoxia for 18 hours. For example, they were seen to up-regulate the cell surface receptors, CXCR4 and GLUT1, and the potent, tumor-promoting cytokines, vascular endothelial growth factor A, interleukin (IL)-1beta and IL-8, adrenomedullin, CXCR4, and angiopoietin-2. Hypoxia also stimulated their expression and/or phosphorylation of various proteins in the nuclear factor-kappaB (NF-kappaB) signaling pathway. We then used both genetic and pharmacologic methods to manipulate the levels of HIFs-1alpha and 2alpha or NF-kappaB in primary macrophages to elucidate their role in the hypoxic induction of many of these key genes. These studies showed that both HIF-1 and -2, but not NF-kappaB, are important transcriptional effectors regulating the responses of macrophages to such a period of hypoxia. Further studies using experimental mouse models are now warranted to investigate the role of such macrophage responses in the progression of various diseased tissues, such as malignant tumors.
 ...
PMID:Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia. 1945 49


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>