Hypoxia upregulates expression of human endosialin gene via hypoxia-inducible factor 2.
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ABSTRACT:
SUBMITTER: Ohradanova A
PROVIDER: S-EPMC2570523 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionHypoxia-inducible factor-1 (HIF1) controls the expression of genes involved in the cellular response to hypoxia. No information is available on its expression in critically ill patients. Thus, we designed the first clinical study in order to evaluate the role of HIF1? as a prognosis marker in patients with shock.Methods50 consecutive adult patients with shock and 11 healthy volunteers were prospectively included. RNA was extracted from whole blood samples and expression of HIF1? was assessed over the first 4 hours of shock. The primary objective was to assess HIF1? as a prognostic marker in shock. Secondary objectives were to evaluate the role of HIF1? as a diagnostic and follow-up marker. Patient survival was evaluated at day 28.ResultsThe causes of shock were sepsis (78%), hemorrhage (18%), and cardiac dysfunction (4%). The HIF1? expression was significantly higher in the shock patients than in the healthy volunteers (121 [72-168] vs. 48 [38-54] normalized copies, p < 0.01), whatever the measured isoforms. It was similar in non-survivors and survivors (108 [range 84-183] vs. 121 [range 72-185] normalized copies, p = 0.92), and did not significantly change within the study period.ConclusionsThe present study is the first to demonstrate the increased expression of HIF1? in patients with shock. Further studies are needed to clarify the potential association with outcome. Our findings reinforce the value of monitoring plasma lactate levels to guide the treatment of shock.
| S-EPMC3580697 | biostudies-literature
Project description:Dermal papilla cells (DPCs) play critical roles in hair follicle development, but the underlying mechanisms that contribute to hair regeneration have yet to be fully elucidated, particularly in terms of alterations in androgenetic alopecia patients. In this study, we demonstrated that hypoxia-inducible factor-1α (HIF-1α) is suppressed in scalp tissues of androgenetic alopecia patients and potentially associated with hair follicle development. Using RT-qPCR and western blot, we found that mRNA and protein levels of trichogenic genes, LEF1 and versican (VCAN), were attenuated in HIF-1α knockdown DPCs. Under an in vivo mimicked environment in a three-dimensional spheroid culture, HIF-1α-suppressed DPCs downregulated the expression of hair induction-related genes. Finally, treatment with a HIF-1α activator resulted in the elevated expression of trichogenic genes in DPCs. This study highlights the importance of dermal HIF-1α expression in regulating trichogenic genes and provides a promising therapeutic target and a fundamental tissue engineering approach for hair loss treatment.
| S-EPMC9883512 | biostudies-literature
Project description:INTRODUCTION:Cxcl12, or stromal-derived factor-1, is a chemokine produced by several hepatic cell types, including hepatocytes, after liver injury and surgical resection. Studies have revealed that Cxcl12 is important for regeneration of the liver after surgical resection and for development of liver fibrosis during chronic liver injury. While the function of Cxcl12 in the liver is well established, the mechanism by which Cxcl12 is upregulated is not fully understood. Because regions of hypoxia develop in the liver following injury, we tested the hypothesis that hypoxia upregulates Cxcl12 in hepatocytes by a hypoxia-inducible factor (HIF)-dependent mechanism. METHODS:To test this hypothesis, primary mouse hepatocytes were isolated from the livers of HIF-1?-deficient mice or HIF-1?-deficient mice and exposed to 1% oxygen. Cxcl12 expression was increased following exposure of primary mouse hepatocytes to 1% oxygen. Previously we have shown, that in addition to HIFs, transforming growth factor-? is required for upregulation of a subset of genes in hypoxic hepatocytes. To examine the role of TGF-? in regulation of Cxcl12 during hypoxia, hepatocytes were pretreated with the TGF-? receptor I inhibitor, SB431542. RESULTS:Upregulation of Cxcl12 by hypoxia was partially prevented in hepatocytes from HIF-1?-deficient mice and completely prevented in hepatocytes from HIF-1?-deficient hepatocytes. This suggests that under hypoxic conditions, both HIF-1? and HIF-2? regulate Cxcl12 in hepatocytes. Pretreatment of hepatocytes with SB431542 completely prevented upregulation Cxcl12 by hypoxia. Further, treatment of hepatocytes with recombinant TGF-?1 upregulated Cxcl12 in hepatocytes cultured in room air. CONCLUSION:Collectively, these studies demonstrate that hypoxia upregulates Cxcl12 in primary mouse hepatocytes by a mechanism that involves HIFs and TGF-?.
| S-EPMC7255688 | biostudies-literature
Project description:Hypoxia-inducible factors (HIFs) 1 and 2 are dimeric ?/? transcription factors that regulate cellular responses to low oxygen. HIF-1 is induced first, whereas HIF-2 is associated with chronic hypoxia. To determine how HIF1A mRNA, the inducible subunit of HIF-1, is regulated during hypoxia, we followed HIF1A mRNA levels in primary HUVECs over 24 hours using quantitative PCR. HIF1A and VEGF A (VEGFA) mRNA, a transcriptional target of HIF-1, increased ? 2.5- and 8-fold at 2-4 hours, respectively. To determine how the mRNAs were regulated, we identified a microRNA (miRNA), miR-429, that destabilized HIF1A message and decreased VEGFA mRNA by inhibiting HIF1A. Target protector analysis, which interferes with miRNA-mRNA complex formation, confirmed that miR-429 targeted HIF1A message. Desferoxamine treatment, which inhibits the hydroxylases that promote HIF-1? protein degradation, stabilized HIF-1 activity during normoxic conditions and elevated miR-429 levels, demonstrating that HIF-1 promotes miR-429 expression. RNA-sequencing-based transcriptome analysis indicated that inhibition of miRNA-429 in HUVECs up-regulated 209 mRNAs, a number of which regulate angiogenesis. The results demonstrate that HIF-1 is in a negative regulatory loop with miR-429, that miR-429 attenuates HIF-1 activity by decreasing HIF1A message during the early stages of hypoxia before HIF-2 is activated, and this regulatory network helps explain the HIF-1 transition to HIF-2 during chronic hypoxia in endothelial cells.
| S-EPMC4396612 | biostudies-literature
Project description:Induction of a series of anti-hypoxic proteins protects cells during exposure to hypoxic conditions. Hypoxia-inducible factor-? (HIF-?) is a major transcription factor that orchestrates this protective effect. To activate HIF exogenously, without exposing cells to hypoxic conditions, many small-molecule inhibitors targeting prolyl hydroxylase domain-containing protein have been developed. In addition, suppression of factor inhibiting HIF-1 (FIH-1) has also been shown to have the potential to activate HIF-?. However, few small-molecule inhibitors of FIH-1 have been developed. In this study, we synthesized a series of furan- and thiophene-2-carbonyl amino acid derivatives having the potential to inhibit FIH-1. The inhibitory activities of these compounds were evaluated in SK-N-BE(2)c cells by measuring HIF response element (HRE) promoter activity. Several furan- and thiophene-2-carbonyl amino acid derivatives inhibited FIH-1 based on correlations among the docking score of the FIH-1 active site, the chemical structure of the compounds, and biological HIF-?/HRE transcriptional activity.
| S-EPMC6017830 | biostudies-literature
Project description:Lysyl oxidase?like 2 (LOXL2), a member of the lysyl oxidase gene family, is involved in the progression of hepatocellular carcinoma progression and metastasis. Increased expression of LOXL2 has been identified in several types of cancer, including hepatocellular carcinoma. Recently, LOXL2 has been reported to promote epithelial?mesenchymal transition by reducing E?cadherin expression via the upregulation of Snail expression. The present study provided evidence demonstrating that LOXL2 inhibited the expression of fructose?1, 6?biphosphatase (FBP1) and enhanced the glycolysis of Huh7 and Hep3B hepatocellular carcinoma cell lines in a Snail?dependent manner. Overexpression of the point?mutated form of LOXL2 [LOXL2(Y689F)], which lacks enzymatic activity, does not affect the expression of Snail1 or FBP1. Notably, targeting extracellular LOXL2 of Huh7 cells with a therapeutic antibody was unable to abolish its regulation on the expression of Snail and FBP1. Knockdown of LOXL2 also interrupted the angiogenesis of Huh7 and Hep3B cells, and this effect could be rescued by the overexpression of Snail. Furthermore, upregulation of hypoxia?inducible factor 1? (HIF?1?) and vascular endothelial growth factor (VEGF) expression was observed in Huh7 and Hep3B cells expressing wild?type LOXL2. Notably, the selective LOXL2 inhibitor LOXL2?IN?1 could upregulate the expression of FBP1 and inhibit the expression of Snail, HIF?1? and VEGF in HCC cells, but not in FBP1?knockdown cells. The results of the present study indicated that the intracellular activity of LOXL2 upregulated HIF?1?/VEGF signaling pathways via the Snail?FBP1 axis, and this phenomenon could be inhibited by LOXL2 inhibition. Collectively, these findings further support that LOXL2 exhibits an important role in the progression of hepatocellular carcinoma and implicates LOXL2 as a potential therapeutic agent for the treatment of this disease.
| S-EPMC7107812 | biostudies-literature
Project description:The divalent metal transporter (DMT1, Slc11a2) is an important molecule for intestinal iron absorption. In the Belgrade (b/b) rat, the DMT1 G185R mutation markedly decreases intestinal iron absorption. We used b/b rats as a model to examine the genes that could be compensatory for decreased iron absorption. When tissue hypoxia was assayed by detecting pimonidazole HCl adducts, the b/b liver and intestine exhibited more adducts than the +/+ rats, suggesting that hypoxia might signal altered gene expression. Total RNA in the crypt-villus bottom (C-pole) and villus top (V-pole) of +/+, b/b, and iron-fed b/b rats was isolated for gene array analyses. In addition, hepatic hepcidin and intestinal hypoxia-inducible factor-α (Hifα) expression were examined. The results showed that expression of hepatic hepcidin was significantly decreased and intestinal Hif2α was significantly increased in b/b and iron-fed b/b than +/+ rats. In b/b rats, the expression of Tfrc mRNA in the C-pole and of DMT1, Dcytb, FPN1, Heph, Hmox1, and ZIP14 mRNAs in the V-pole were markedly enhanced with increases occurring even in the C-pole. After iron feeding, the increased expression found in b/b rats persisted, except for Heph and ZIP14, which returned to normal levels. Thus in b/b rats depressed liver hepcidin production and activated intestinal Hif2α starting at the C-pole resulted in increasing expression of iron transport genes, including DMT1 G185R, in an attempt to compensate for the anemia in Belgrade rats.
| S-EPMC3129931 | biostudies-literature
Project description:Iron demand in bone marrow increases when erythropoiesis is stimulated by hypoxia via increased erythropoietin (EPO) synthesis in kidney and liver. Hepcidin, a small polypeptide produced by hepatocytes, plays a central role in regulating iron uptake by promoting internalization and degradation of ferroportin, the only known cellular iron exporter. Hypoxia suppresses hepcidin, thereby enhancing intestinal iron uptake and release from internal stores. While HIF, a central mediator of cellular adaptation to hypoxia, directly regulates renal and hepatic EPO synthesis under hypoxia, the molecular basis of hypoxia/HIF-mediated hepcidin suppression in the liver remains unclear. Here, we used a genetic approach to disengage HIF activation from EPO synthesis and found that HIF-mediated suppression of the hepcidin gene (Hamp1) required EPO induction. EPO induction was associated with increased erythropoietic activity and elevated serum levels of growth differentiation factor 15. When erythropoiesis was inhibited pharmacologically, Hamp1 was no longer suppressed despite profound elevations in serum EPO, indicating that EPO by itself is not directly involved in Hamp1 regulation. Taken together, we provide in vivo evidence that Hamp1 suppression by the HIF pathway occurs indirectly through stimulation of EPO-induced erythropoiesis.
| S-EPMC3533545 | biostudies-literature
Project description:PurposeNicotine, the major component in cigarette smoke, can promote tumor growth and angiogenesis in various cancers, including lung cancer. Hypoxia-inducible factor-1alpha (HIF-1alpha) is overexpressed in human lung cancers, particularly in non-small cell lung cancers (NSCLC), and is closely associated with an advanced tumor grade, increased angiogenesis, and resistance to chemotherapy and radiotherapy. The purpose of this study was to investigate the effects of nicotine on the expression of HIF-1alpha and its downstream target gene, vascular endothelial growth factor (VEGF), in human lung cancer cells.Experimental designHuman NSCLC cell lines A549 and H157 were treated with nicotine and examined for expression of HIF-1alpha and VEGF using Western blot or ELISA. Loss of HIF-1alpha function using specific small interfering RNA was used to determine whether HIF-1alpha is directly involved in nicotine-induced tumor angiogenic activities, including VEGF expression, cancer cell migration, and invasion.ResultsNicotine increased HIF-1alpha and VEGF expression in NSCLC cells. Pharmacologically blocking nicotinic acetylcholine receptor-mediated signaling cascades, including the Ca2+/calmodulin, c-Src, protein kinase C, phosphatidylinositol 3-kinase, mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2, and the mammalian target of rapamycin pathways, significantly attenuated nicotine-induced up-regulation of HIF-1alpha protein. Functionally, nicotine potently stimulated in vitro tumor angiogenesis by promoting tumor cell migration and invasion. These proangiogenic and invasive effects were partially abrogated by treatment with small interfering RNA specific for HIF-1alpha.ConclusionThese findings identify novel mechanisms by which nicotine promotes tumor angiogenesis and metastasis and provide further evidences that HIF-1alpha is a potential anticancer target in nicotine-associated lung cancer.
| S-EPMC4166418 | biostudies-literature
Project description:Neovascular and degenerative diseases of the eye are leading causes of impaired vision and blindness in the world. Hypoxia or reduced oxygen tension is considered central to the pathogenesis of these disorders. Although the CD36 scavenger receptor features prominently in ocular homeostasis and pathology, little is known regarding its modulation by hypoxia. Herein we investigated the role and regulation of CD36 by hypoxia and by the major hypoxia effector, hypoxia-inducible factor (HIF)-1. In vivo, hypoxia markedly induced CD36 mRNA in corneal and retinal tissue. Subsequent experiments on human retinal pigment epithelial cells revealed that hypoxia time-dependently increased CD36 mRNA, protein, and surface expression; these responses were reliant upon reactive oxygen species production. As an important novel finding, we demonstrate that hypoxic stimulation of CD36 is mediated by HIF-1; HIF-1alpha down-regulation abolished CD36 induction by both hypoxia and cobalt chloride. Sequence analysis of the human CD36 promoter region revealed a functional HIF-1 binding site. A luciferase reporter construct containing this promoter fragment was activated by hypoxia, whereas mutation at the HIF-1 consensus site decreased promoter activation. Specific binding of HIF-1 to this putative site in hypoxic cells was detected by a chromatin immunoprecipitation assay. Interestingly, inhibition of the phosphatidylinositol 3-kinase pathway blocked the hypoxia-dependent induction of CD36 expression and promoter activity. Functional ramifications of CD36 hypoxic accumulation were evinced by CD36-dependent increases in scavenging and anti-angiogenic activities. Together, our findings indicate a novel mechanism by which hypoxia induces CD36 expression via activation of HIF-1 and the phosphatidylinositol 3-kinase pathway.
| S-EPMC2785357 | biostudies-literature