Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hypoxia-inducible factors HIF-1 alpha and HIF-2 alpha are structurally similar as regards their DNA-binding and dimerization domains, but differ in their transactivation domains and, as is shown by experiments using hif-1 alpha(-/-) and hif-2 alpha(-/-) mice, in their functions. This implies that HIF-1 alpha and HIF-2 alpha may have unique target genes. To address this discrepancy and identify HIF-2 alpha-specific target genes, we performed yeast two-hybrid analysis and identified the tumor suppressor Int6/eIF3e/p48 as a novel target gene product involved in HIF-2 alpha regulation. The int6 gene was first identified from a screen in which the mouse mammary tumor virus was employed as an insertional mutagen to identify genes whose functions are critical for breast tumor formation. Here, by using two-hybrid analysis, immunoprecipitation in mammalian cells, and HRE-reporter assays, we report the specific interaction of HIF-2 alpha (but not HIF-1 alpha or HIF-3 alpha) with Int6. The results indicate that the direct interaction of Int6 induces proteasome inhibitor-sensitive HIF-2 alpha degradation. This degradation was clearly observed in renal cell carcinoma 786-O cells, and was found to be both hypoxia- and pVHL-independent. Furthermore, Int6 protein knockdown by int6-siRNA vectors or the dominant-negative mutant Int6-Delta C increased endogenous HIF-2 alpha expression, even under normoxia, and induced sets of critical angiogenic factors comprising vascular endoplasmic growth factor, angiopoietin, and basic fibroblast growth factor mRNA. These results indicate that Int6 is a novel and critical determinant of HIF-2 alpha-dependent angiogenesis as well as cancer formation, and that int6-siRNA transfer may be an effective therapeutic strategy in pathological conditions such as heart and brain ischemia, hepatic cirrhosis, and obstructive vessel diseases.
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PMID:Mammalian tumor suppressor Int6 specifically targets hypoxia inducible factor 2 alpha for degradation by hypoxia- and pVHL-independent regulation. 1732 24

This study was designed to determine the effect of L-arginine on hypoxia inducible factor alpha (HIF-1 alpha) and Sonic hedgehog (Shh) levels considered to be involved in the development of ischemia/reperfusion (I/R) injury. Unilaterally nephrectomized Sprague-Dawley rats were subjected to 60 minutes of left renal ischemia followed by 45 minutes of reperfusion. Group 1 were sham-operated animals; group 2, I-R/Untreated animals; and group 3, I-R/L-Arg-treated animals. Serum creatinine, blood urea nitrogen (BUN), and kidney malondialdehyde (MDA) levels were determined as well as examining the kidneys histologically. The treatment of rats with L-Arg produced a significant reduction in the levels of BUN, creatinine, MDA, and histopathological score compared to renal I/R groups. The Shh expression in the tubulus epithelia were intensely increased in the I-R/L-Arg group when compared to that of the Sham-control and the I-R/untreated groups. Additionally, the HIF-1alpha expression in the tubulus epithelia and the interstitial spaces were intensely increased in the I-R/L-Arg group. These findings suggest that NO reduces the renal dysfunction associated with I/R of the kidney and may act as a trigger to induce Shh and HIF-1 activity.
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PMID:Nitric oxide regulates expression of sonic hedgehog and hypoxia-inducible factor-1alpha in an experimental model of kidney ischemia-reperfusion. 1749 36

Hypoxia inducible factor-1 alpha (HIF-1 alpha) is a key determinant of oxygen-dependent gene regulation in angiogenesis. HIF-1 alpha overexpression may be beneficial in cell therapy of hypoxia-induced pathophysiological processes, such as ischemic heart disease. To address this issue, human peripheral blood mononuclear cells (PBMNCs) were induced to differentiate into endothelial progenitor cells (EPCs), and then were transfected with either an HIF-1 alpha-expressing or a control vector and cultured under normoxia or hypoxia. Hypoxia-induced HIF-1 alpha mRNA and protein expression was increased after HIF-1 alpha transfection. This was accompanied by VEGF mRNA induction and increased VEGF secretion. Hypoxia-stimulated VEGF mRNA induction was significantly abrogated by HIF-1 alpha-specific siRNA. Functional studies showed that HIF-1 alpha overexpression further promoted hypoxia-induced EPC differentiation, proliferation and migration. The expressions of endothelial cell markers CD31, VEGFR2 (Flk-1) and eNOS as well as VEGF and NO secretions were also increased. Furthermore, in an in vivo model of hindlimb ischemia, HIF-1 alpha-transfected EPCs homed to the site of ischemia. A higher revascularization potential was also demonstrated by increased capillary density at the injury site. Our results revealed that endothelial progenitor cells ex vivo modification by hypoxia inducible factor-1 alpha gene transfection is feasible and may offer significant advantages in terms of EPC expansion and treatment efficacy.
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PMID:Angiogenesis by transplantation of HIF-1 alpha modified EPCs into ischemic limbs. 1754 46

The transcription factor hypoxia-inducible factor-1 (HIF-1) regulates the expression of more than 100 genes involved in cellular adaptation and survival under hypoxic stress. Activation of HIF-1 is associated with numerous physiological and pathological processes that include tumorigenesis, vascular remodelling, inflammation, and hypoxia/ischemia-related tissue damage. Experimental data support the concept that modulation of Reactive Oxygen Species (ROS) levels have an important impact on the hypoxic response mediated by HIF-1 alpha. However, ROS generation, the exact kinetics and conditions of ROS production and their specific relevance to HIF-l alpha activation are issue still to be clarified. Clinical studies suggested that HIF-1 activation correlates directly with advanced disease stages and treatment resistance among cancer patients. Preclinical studies support the inhibition of HIF-1 as a major molecular target for anti-tumour drug discovery. Considerable effort is underway to identify therapeutically useful molecule HIF-1 inhibitors. Most of the compounds discovered to inhibit HIF-1 are natural products or synthetic compounds with structures that are based on natural product leads. Natural products have also served a vital role as molecular probes to elucidate the pathways that regulate HIF-1 activity. Many of the substances found to inhibit HIF-I are non-druggable compounds that are too cytotoxic to serve as drug leads. The application of high-throughput screening methods, complementary molecular-targeted assays, and structurally diverse chemical libraries hold promise for the discovery of therapeutically useful HIF-1 inhibitors.
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PMID:Cellular redox status regulates hypoxia inducible factor-1 activity. Role in tumour development. 1755 Jan 31

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.
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PMID:The effect of 2-methoxyestradiol, a HIF-1 alpha inhibitor, in global cerebral ischemia in rats. 1771 91

Hypoxia occurs in cancer, prolonged exercise, and long-term ischemia with durations of several hours or more, and the hypoxia-inducible factor 1 (HIF1) pathway response to these conditions differs from responses to transient hypoxia. We used computational modeling, validated by experiments, to gain a quantitative, temporal understanding of the mechanisms driving HIF1 response. To test the hypothesis that HIF1 alpha protein levels during chronic hypoxia are tightly regulated by a series of molecular feedbacks, we took into account protein synthesis and product inhibition, and analyzed HIF1 system changes in response to hypoxic exposures beyond 3 to 4 h. We show how three autocrine feedback loops together regulate HIF 1 alpha hydroxylation in different microenvironments. Results demonstrate that prolyl hydroxylase, succinate and HIF1 alpha feedback determine intracellular HIF1 alpha levels over the course of hours to days. The model provides quantitative insight critical for characterizing molecular mechanisms underlying a cell's response to long-term hypoxia.
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PMID:Three autocrine feedback loops determine HIF1 alpha expression in chronic hypoxia. 1772 Feb 60

The ubiquitin-proteasome system is the major non-lysosymal system for degrading proteins in the cell; the work leading to its discovery was awarded the Nobel Prize in Chemistry in 2004. In addition to small ubiquitin-like modifiers (e.g. Sumo and Nedd8), ubiquitin is involved in the complex regulation of the levels and function of many proteins and signaling pathways involved in determining cell fate. The cell death regulatory proteins, such as Bcl-2 family proteins and caspases are targeted for degradation by the ubiquitin proteasome system (UPS). In addition to mediating the degradation of proteins, the UPS regulates function and translocation of proteins, many of which play a role in the determination of cell fate. For example the UPS can regulate the activity of transcription factors, such as P53, NF-kappaB and HIF-1 alpha, which control the expression of protein mediators of cell death. Aberrant UPS function has been reported in multiple neuropathologies including Parkinson's diseases and ischemia. With the number of ubiquitin conjugating and de-conjugating enzymes reaching close to the levels of protein kinases and phosphatases, it is clear that ubiquitination is an important biological regulatory step for proteins.
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PMID:Ubiquitin-proteasome system as a modulator of cell fate. 1798 2

Hypoxia inducible factor 1 alpha (HIF-1 alpha) is a key regulator of cellular oxygen homeostasis. However, the regulation of HIF-1 alpha in neonates with hypoxia-ischemia (HI) is not clear. Under normoxic conditions, the extracellular signal-related protein kinase (ERK) pathway has been shown to be involved in the activation of HIF-1 alpha in cell lines. Therefore, we hypothesized that the ERK pathway is involved in the activation of HIF-1 alpha and its target genes in the developing rat brain following HI. To test this hypothesis, we set up an HI model by ligating the right common carotid artery followed by hypoxia using postnatal day 10 rats. Rat brains from HI and sham controls were collected to detect the expression of HIF-1 alpha, its target gene, vascular endothelial growth factor (VEGF), and ERK using immunohistochemistry, Western blot analysis, and RT-PCR. We found that the expression of HIF-1 alpha protein was significantly upregulated at 4 h and peaked at 8 h after HI compared with sham controls. Accordingly, VEGF was similarly upregulated. However, the expression of total ERK (Erk1/2) had no obvious changes. Even though the phosphorylated form of ERK, p-Erk1/2, was upregulated and peaked at 4 h after HI, it is earlier than that seen in HIF-1 alpha expression. Furthermore, the induction of HIF-1 alpha protein, but not its mRNA, could be significantly inhibited by Erk1/2 pathway specific inhibitor, U0126. Our findings suggest that Erk1/2 pathway is involved in the regulation of HIF-1 alpha and VEGF in the developing rat brain after HI. The Erk1/2 pathway may work as a potential target for therapeutic intervention in neonates with HI.
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PMID:The requirement of extracellular signal-related protein kinase pathway in the activation of hypoxia inducible factor 1 alpha in the developing rat brain after hypoxia-ischemia. 1821 Jan 38

Ischemia-reperfusion reduces the negative functional effects of cyclic GMP in cardiac myocytes. In this study, we tested the hypothesis that upregulation of hypoxic inducible factor-1 (HIF-1) would improve the actions of cyclic GMP signaling following simulated ischemia-reperfusion. HIF-1 alpha was increased with deferoxamine (150 mg/kg for 2 days). Rabbit cardiac myocytes were subjected to simulated ischemia [15 min 95% N(2)-5% CO(2)] and reperfusion [reoxygenation] to produce myocyte stunning. Cell function was measured utilizing a video-edge detector. Shortening was examined at baseline and after brain natriuretic peptide (BNP, 10(-8), 10(-7)M) or S-nitroso-N-acetyl-penicillamine (SNAP, 10(-6), 10(-5)M) followed by KT5823 (cyclic GMP protein kinase inhibitor, 10(-6)M). Kinase activity was measured via a protein phosphorylation assay. Under control conditions, BNP (-30%) and SNAP (-41%) reduced percent shortening, while KT5823 partially restored function (+18%). Deferoxamine treated control myocytes responded similarly. In stunned myocytes, BNP (-21%) and SNAP (-25%) reduced shortening less and KT5823 did not increase function (+2%). Deferoxamine increased the effects of BNP (-38%) and SNAP (-41%) in stunning and restored the effects of KT5823 (+12%). The cyclic GMP protein kinase increased phosphorylation of several proteins in control HIF-1 +/- cells. Phosphorylation was reduced in stunned cells and was restored in deferoxamine treated stunned cells. This study demonstrated that simulated ischemia-reperfusion reduced the negative functional effects of increasing cyclic GMP and this was related to reduced effects of the cyclic GMP protein kinase. Increased HIF-1 alpha protects the functional effects of cyclic GMP thorough maintenance of cyclic GMP protein kinase activity after ischemic-reperfusion.
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PMID:Hypoxia inducible factor-1 improves the actions of nitric oxide and natriuretic peptides after simulated ischemia-reperfusion. 1845 49

The aim of this study was to characterize the molecular and histological changes that occur in the retina following central retinal artery occlusion (CRAO) in a mouse model. CRAO was induced in 60 mice by laser photoactivation of intravenously injected rose bengal. Mice were sacrificed at 3, 6, 12, and 24h and 7 and 21 days after CRAO induction for molecular analysis (5-13 mice/time point) and histological and apoptosis studies (3-4 mice/time point). Fundus examination and fluorescein angiography were also performed at various points. Retinal mRNA was analyzed for expression of T-cell antigen 1 (Thy-1), vascular endothelial growth factor (VEGF), heme oxygenase-1 (HO-1), and hypoxia-induced factor 1 alpha (HIF-1 alpha) using real-time polymerase chain reaction. The results showed that at 6-24h following CRAO induction, the retina was edematous, with interrupted blood perfusion. Fluorescein angiography showed reperfusion at 6h, and TdT-mediated dUTP nick end-labeling (TUNEL) assay revealed an increase in apoptotic cells in the first 24h. On histological sections, nuclear loss in the inner retinal layers was maximal on day 21. Thy-1 expression decreased to 30% of baseline (P<or=0.002). VEGF expression increased in the first 3h and gradually decreased thereafter, reaching 75% of baseline on day 21 (P<or=0.005). HO-1 was upregulated at all time points, with a peak at 12h. No change was noted in HIF-1 alpha expression at any time. In conclusion, CRAO in mice causes cell apoptosis in the inner layers of the retina, with a significant cell loss and a decrease in Thy-1 expression by 21 days. These changes are accompanied by a rise in expression of the ischemia-related protein HO-1 to a peak at 12h, with levels remaining above control values at day 21. Given the similarity of the mouse model to human CRAO, these findings may have implications for the future clinical management of CRAO.
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PMID:Molecular and histological changes following central retinal artery occlusion in a mouse model. 1863 47


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