Up-regulation of hypoxia-inducible factor-1 alpha by cobalt chloride prevents hearing loss in noise-exposed mice

2011 ◽  
Vol 31 (1) ◽  
pp. 153-159 ◽  
Author(s):  
Jong Woo Chung ◽  
Jung-Eun Shin ◽  
Kwang Woo Han ◽  
Joong Ho Ahn ◽  
Young-Jin Kim ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Cobalt Chloride ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1

scholarly journals Obesity and Oral Contraceptives Synergistically Increase Thrombotic Risk By Downregulating Protein S

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4237-4237
Author(s):  
Lekha Thangada ◽  
Manoj Kumar ◽  
Satish Sekhar Pilli ◽  
Rinku Majumder
Keyword(s):  
Oral Contraceptives ◽  
Cobalt Chloride ◽  
Conflicts Of Interest ◽  
Hypoxia Inducible Factor ◽  
Protein S ◽  
Immunoblot Analysis ◽  
Thrombotic Risk ◽  
Hypoxia Inducible Factor 1 ◽  
Two Factors ◽  
Major Producer

Abstract Background: The increased thrombotic effects of estrogen-based oral contraceptives and obesity have been documented independently. However, obesity and oral contraceptives combined are associated with a far greater thrombotic risk, but we have a poor understanding of the mechanism of this greater effect. Increasingly, women are using oral contraceptives, and the national obesity rate has been skyrocketing. Thus, it is imperative to explain how obesity and oral contraceptives work together to significantly elevate thrombotic risk. We know that hypoxia-inducible factor 1-ɑ (HIF-1ɑ) and the estrogen receptor (Erɑ) bind to the promoter of the Protein S gene; binding occurs at sites within ~450 nucleotides of each other, and the two transcription factors downregulate Protein S expression independently. We hypothesize that the two factors, by binding the promoter simultaneously, synergistically downregulate Protein S to a degree much greater than the downregulation mediated by each factor separately. Aims: The goal of this project is determining whether estrogen and obesity-induced hypoxia work synergistically to downregulate Protein S transcription and increase thrombotic risk. Methods: We measured the effects of obesity and oral contraceptives on hepatocarcinoma (HEP G2) cells because the liver is the major producer of Protein S. Estrogen of varying concentrations (25-150 μM) was used to mimic the effects of oral contraceptives, and cobalt chloride of varying concentrations (25-150 μM) was used to stimulate hypoxia and HIF-1ɑ expression. Cells were exposed to estrogen only, cobalt chloride only, and estrogen and cobalt chloride together for 24 hours, after which the cells were harvested and subjected to q-PCR and immunoblot blot analyses to measure Protein S transcription and protein expression. Although cobalt chloride is a reliable inducer of hypoxia and HIF-1ɑ expression, we also performed hypoxia experiments by incubating cells in a chamber with varying O 2 concentrations (20%, 15%, 10%, 5%, 1%). Results and Conclusions: Immunoblot analysis of cells treated with either CoCl 2 and estrogen supplementation revealed a ~20% reduction in Protein S levels compared to control conditions and a more significant reduction in (~60%) Protein S expression in cells treated with estrogen and CoCl 2 together. These results supported our hypothesis that obesity and estrogen-based contraceptives increase thrombotic risk by downregulating anticoagulant Protein S transcription and subsequently decreasing Protein S level. Disclosures No relevant conflicts of interest to declare.

Copper-dependent and -independent hypoxia-inducible factor-1 regulation of gene expression

Metallomics ◽  
2014 ◽  
Vol 6 (10) ◽  
pp. 1889-1893 ◽  
Author(s):  
Zhen Zhang ◽  
Liying Qiu ◽  
Chen Lin ◽  
Hong Yang ◽  
Haiying Fu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cobalt Chloride ◽  
Regulation Of Gene Expression ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1

HIF-1 mediated expression of BNIP3 by cobalt chloride is Cu-dependent, but the expression of IGF-2 is Cu-independent.

scholarly journals HIF-1 regulates hypoxia- and insulin-induced expression of apelin in adipocytes

2007 ◽  
Vol 293 (6) ◽  
pp. E1590-E1596 ◽  
Author(s):  
Alexander J. Glassford ◽  
Patrick Yue ◽  
Ahmad Y. Sheikh ◽  
Hyung J. Chun ◽  
Shirin Zarafshar ◽  
...  
Keyword(s):  
Insulin Signaling ◽  
Cobalt Chloride ◽  
Hypoxia Inducible Factor ◽  
Metabolic Responses ◽  
Quantitative Real Time Pcr ◽  
Mouse Embryonic Fibroblasts ◽  
Embryonic Fibroblasts ◽  
Targeted Deletion ◽  
Hypoxia Inducible Factor 1

Apelin, a novel peptide with significant cardioactive properties, is upregulated by insulin in adipocytes. However, the mechanism by which insulin promotes apelin production is unknown. Hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor involved in the angiogenic and metabolic responses to tissue hypoxia, has been shown to be activated by insulin in various settings. We therefore hypothesized that HIF-1 regulates insulin-mediated apelin expression in adipocytes. 3T3-L1 cells were differentiated into adipocytes in culture. For experiments, serum-starved 3T3-L1 cells were exposed to insulin and/or a 1% O2 environment. Apelin expression was assessed using quantitative real-time PCR and ELISA. To directly assess the role of HIF-1 in apelin production, we differentiated mouse embryonic fibroblasts (MEFs) containing a targeted deletion of the HIF-1α gene into adipocytes and measured their response to insulin and hypoxia. Apelin expression in mature 3T3-L1 adipocytes was increased significantly by insulin and was attenuated by pharmacological inhibition of insulin signaling. Exposure of cells to either hypoxia or the chemical HIF activators cobalt chloride (CoCl2) and dimethyloxaloylglycine (DMOG) resulted in significant upregulation of apelin, consistent with a role for HIF in apelin induction. Moreover, hypoxia-, CoCl2-, DMOG-, and insulin-induced apelin expression were all attenuated in differentiated HIF-1α-deficient MEFs. In summary, in cultured 3T3-L1 adipocytes and differentiated MEFs, HIF-1 appears to be involved in hypoxia- and insulin-induced apelin expression.

scholarly journals Desferrioxamine induces erythropoietin gene expression and hypoxia- inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction

Blood ◽  
1993 ◽  
Vol 82 (12) ◽  
pp. 3610-3615 ◽  
Author(s):  
GL Wang ◽  
GL Semenza
Keyword(s):  
Signal Transduction ◽  
Dna Binding ◽  
Cobalt Chloride ◽  
De Novo ◽  
Hypoxia Inducible Factor ◽  
Binding Activity ◽  
Ferrous Ammonium Sulfate ◽  
Hypoxia Inducible Factor 1 ◽  
Dna Binding Activity ◽  
Hep3b Cells

Abstract Erythropoietin (EPO) gene transcription is activated in kidney cells in vivo and in Hep3B cells exposed to hypoxia or cobalt chloride. Hypoxia- inducible factor 1 (HIF-1) is a nuclear factor that binds to the hypoxia-inducible enhancer of the EPO gene at a site that is required for transcriptional activation. HIF-1 DNA-binding activity is induced by hypoxia or cobalt chloride treatment of Hep3B cells. We report that treatment of Hep3B cells with desferrioxamine (DFX) induced HIF-1 activity and EPO RNA expression with kinetics similar to the induction of HIF-1 by hypoxia or cobalt chloride. Induction by each of these stimuli was inhibited by cycloheximide, indicating a requirement for de novo protein synthesis. DFX appears to induce HIF-1 by chelating iron as induction was inhibited by coadministration of ferrous ammonium sulfate. DFX administration to mice transiently increased EPO RNA levels in the kidney. As previously shown for hypoxia and cobalt treatment, DFX also induced HIF-1 activity in non-EPO-producing cells, suggesting the existence of a common hypoxia signal-transduction pathway leading to HIF-1 induction in different cell types.

scholarly journals Desferrioxamine induces erythropoietin gene expression and hypoxia- inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction

Blood ◽  
1993 ◽  
Vol 82 (12) ◽  
pp. 3610-3615 ◽  
Author(s):  
GL Wang ◽  
GL Semenza
Keyword(s):  
Signal Transduction ◽  
Dna Binding ◽  
Cobalt Chloride ◽  
De Novo ◽  
Hypoxia Inducible Factor ◽  
Binding Activity ◽  
Ferrous Ammonium Sulfate ◽  
Hypoxia Inducible Factor 1 ◽  
Dna Binding Activity ◽  
Hep3b Cells

Erythropoietin (EPO) gene transcription is activated in kidney cells in vivo and in Hep3B cells exposed to hypoxia or cobalt chloride. Hypoxia- inducible factor 1 (HIF-1) is a nuclear factor that binds to the hypoxia-inducible enhancer of the EPO gene at a site that is required for transcriptional activation. HIF-1 DNA-binding activity is induced by hypoxia or cobalt chloride treatment of Hep3B cells. We report that treatment of Hep3B cells with desferrioxamine (DFX) induced HIF-1 activity and EPO RNA expression with kinetics similar to the induction of HIF-1 by hypoxia or cobalt chloride. Induction by each of these stimuli was inhibited by cycloheximide, indicating a requirement for de novo protein synthesis. DFX appears to induce HIF-1 by chelating iron as induction was inhibited by coadministration of ferrous ammonium sulfate. DFX administration to mice transiently increased EPO RNA levels in the kidney. As previously shown for hypoxia and cobalt treatment, DFX also induced HIF-1 activity in non-EPO-producing cells, suggesting the existence of a common hypoxia signal-transduction pathway leading to HIF-1 induction in different cell types.

Vascular adaptations to hypoxia: molecular and cellular mechanisms regulating vascular tone

2007 ◽  
Vol 43 ◽  
pp. 105-120 ◽  
Author(s):  
Michael L. Paffett ◽  
Benjimen R. Walker
Keyword(s):  
Vascular Tone ◽  
Cellular Proliferation ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Hypoxia Inducible Factor ◽  
Systemic Circulation ◽  
Cellular Mechanisms ◽  
Hypoxia Inducible Factor 1 ◽  
Pulmonary Vasoconstriction ◽  
Adaptive Mechanisms ◽  
Adaptive Processes

Several molecular and cellular adaptive mechanisms to hypoxia exist within the vasculature. Many of these processes involve oxygen sensing which is transduced into mediators of vasoconstriction in the pulmonary circulation and vasodilation in the systemic circulation. A variety of oxygen-responsive pathways, such as HIF (hypoxia-inducible factor)-1 and HOs (haem oxygenases), contribute to the overall adaptive process during hypoxia and are currently an area of intense research. Generation of ROS (reactive oxygen species) may also differentially regulate vascular tone in these circulations. Potential candidates underlying the divergent responses between the systemic and pulmonary circulations may include Nox (NADPH oxidase)-derived ROS and mitochondrial-derived ROS. In addition to alterations in ROS production governing vascular tone in the hypoxic setting, other vascular adaptations are likely to be involved. HPV (hypoxic pulmonary vasoconstriction) and CH (chronic hypoxia)-induced alterations in cellular proliferation, ionic conductances and changes in the contractile apparatus sensitivity to calcium, all occur as adaptive processes within the vasculature.

TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Cancer Progression ◽  
Hypoxia Inducible Factor ◽  
Tumor Hypoxia ◽  
Human Lung Cancer ◽  
Regulatory Subunit ◽  
Patients With Cancer ◽  
Hypoxia Inducible Factor 1 ◽  
Chemically Induced ◽  
Induced Tumors ◽  
Patient Prognosis

Tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) activationare associated with cancer progression. Here, we demonstrate thatthe transcription factor TAp73 opposes HIF-1 activity through anontranscriptional mechanism, thus affecting tumor angiogenesis.TAp73-deficient mice have an increased incidence of spontaneousand chemically induced tumors that also display enhanced vascularization.Mechanistically, TAp73 interacts with the regulatory subunit(α) of HIF-1 and recruits mouse double minute 2 homolog intothe protein complex, thus promoting HIF-1α polyubiquitination andconsequent proteasomal degradation in an oxygen-independentmanner. In human lung cancer datasets, TAp73 strongly predictsgood patient prognosis, and its expression is associated with lowHIF-1 activation and angiogenesis. Our findings, supported by invivo and clinical evidence, demonstrate a mechanism for oxygenindependentHIF-1 regulation, which has important implicationsfor individualizing therapies in patients with cancer.

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