scholarly journals Intermittent hypoxia enhances the expression of HIF1A by increasing the quantity and catalytic activity of KDM4A-C and demethylating H3K9me3 at the HIF1A locus

2021 ◽  
Author(s):  
Chloe-Anne Martinez ◽  
Neha Bal ◽  
Peter A Cistulli ◽  
Kristina M Cook
Keyword(s):  
Intermittent Hypoxia ◽  
Target Genes ◽  
Chronic Hypoxia ◽  
Oxygen Sensing ◽  
Biological Effects ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1 ◽  
Sensing Systems ◽  
Cellular Oxygen ◽  
Fine Tune

Cellular oxygen-sensing pathways are primarily regulated by hypoxia inducible factor-1 (HIF-1) in chronic hypoxia and are well studied. Intermittent hypoxia also occurs in many pathological conditions, yet little is known about its biological effects. In this study, we investigated how two proposed cellular oxygen sensing systems, HIF-1 and KDM4A-C, respond to cells exposed to intermittent hypoxia and compared to chronic hypoxia. We found that intermittent hypoxia increases HIF-1 activity through a pathway distinct from chronic hypoxia, involving the KDM4A, -B and -C histone lysine demethylases. Intermittent hypoxia increases the quantity and activity of KDM4A-C resulting in a decrease in H3K9 methylation. This contrasts with chronic hypoxia, which decreases KDM4A-C activity, leading to hypermethylation of H3K9. Demethylation of histones bound to the HIF1A gene in intermittent hypoxia increases HIF1A mRNA expression, which has the downstream effect of increasing overall HIF-1 activity and expression of HIF target genes. This study highlights how multiple oxygen-sensing pathways can interact to regulate and fine tune the cellular hypoxic response depending on the period and length of hypoxia.

n-Propyl gallate activates hypoxia-inducible factor 1 by modulating intracellular oxygen-sensing systems

2008 ◽  
Vol 411 (1) ◽  
pp. 97-105 ◽  
Author(s):  
Motohide Kimura ◽  
Satoshi Takabuchi ◽  
Tomoharu Tanaka ◽  
Miyahiko Murata ◽  
Kenichiro Nishi ◽  
...  
Keyword(s):  
Propyl Gallate ◽  
Transcriptional Activity ◽  
Target Genes ◽  
Cultured Cells ◽  
Oxygen Sensing ◽  
Hypoxia Inducible Factor ◽  
Downstream Target ◽  
Hypoxia Inducible Factor 1

HIF-1 (hypoxia-inducible factor 1) is a master regulator of cellular adaptive responses to hypoxia. The expression and transcriptional activity of the HIF-1α subunit is stringently controlled by intracellular oxygen tension through the action of prolyl and asparaginyl hydroxylases. In the present study we demonstrate that PG (n-propyl gallate) activates HIF-1 and expression of its downstream target genes under normoxic conditions in cultured cells and in mice. The stability and transcriptional activity of HIF-1α are increased by PG. PG treatment inhibits the interaction between HIF-1α and VHL (von Hippel–Lindau protein) and promotes the interaction between HIF-1α and p300, indicating that PG inhibits the activity of both prolyl and asparaginyl HIF-1α hydroxylases. We conclude that PG activates HIF-1 and enhances the resultant gene expression by directly affecting the intracellular oxygen sensing system in vitro and in vivo and that PG represents a lead compound for the development of a non-toxic activator of HIF-1.

scholarly journals An integrative genomics approach identifies Hypoxia Inducible Factor-1 (HIF-1)-target genes that form the core response to hypoxia

2009 ◽  
Vol 37 (14) ◽  
pp. 4587-4602 ◽  
Author(s):  
Yair Benita ◽  
Hirotoshi Kikuchi ◽  
Andrew D. Smith ◽  
Michael Q. Zhang ◽  
Daniel C. Chung ◽  
...  
Keyword(s):  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Integrative Genomics ◽  
Hypoxia Inducible Factor 1 ◽  
The Core

scholarly journals Accelerated tumor growth under intermittent hypoxia is associated with hypoxia-inducible factor-1-dependent adaptive responses to hypoxia

Oncotarget ◽  
2017 ◽  
Vol 8 (37) ◽  
pp. 61592-61603 ◽  
Author(s):  
Dae Wui Yoon ◽  
Daeho So ◽  
Sra Min ◽  
Jiyoung Kim ◽  
Mingyu Lee ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Intermittent Hypoxia ◽  
Hypoxia Inducible Factor ◽  
Adaptive Responses ◽  
Hypoxia Inducible Factor 1

scholarly journals Down-regulation of microRNA-31 suppresses hepatic fibrosis induced by carbon tetrachloride

2020 ◽  
Vol 18 ◽  
pp. 205873922094263
Author(s):  
Bing Deng ◽  
Detao Tang ◽  
Yong Qiang ◽  
Xiang Zheng
Keyword(s):  
Carbon Tetrachloride ◽  
Olive Oil ◽  
Hepatic Fibrosis ◽  
Biological Effects ◽  
Hypoxia Inducible Factor ◽  
Related Factor ◽  
Related Factors ◽  
Altered Expression ◽  
Cell Functions ◽  
Hypoxia Inducible Factor 1

MicroRNA-31 (miR-31) is among the most frequently altered microRNAs in human diseases, and altered expression of miR-31 has been detected in a large variety of diseases types. miR-31 could also regulate a variety of cell functions including hepatic fibrosis. Hepatic stellate cells (HSCs) are regarded as the major cell type involved in hepatic fibrosis. Male BALB/c mice (five mice per group aged 6 weeks) received 200 μL of body weight of carbon tetrachloride (10% CCl4) mixed with olive oil intraperitoneally, and the first dose was doubled. To induce hepatic fibrosis, carbon tetrachloride was injected twice a week for 4, 6, 8, and 10 weeks. Control animals were injected with an equal volume of olive oil at the same time intervals. We found that miR-31 expression and fibrosis-related factors in four hepatic fibrosis stages. However, we noted that inhibition of miR-31 was down-regulated fibrosis-related factor expression in F1–F3 stages, but no F4 stage. Thus, we hypothesize that miR-31 may mediate hepatic fibrosis. In this research, we found that inhibition of miR-31 expression significantly inhibited HSC activation. The biological function of miR-31 during HSC activation might be through targeting hypoxia-inducible factor 1-alpha inhibitor (HIF1AN). Inhibition of miR-31 can reduce the transcription factor activity of hypoxia inducible factor 1 (HIF-1) by targeting the biological effects of HIF1AN with the condition of hypoxia. In later hepatic fibrosis could be rescue combining with inhibition of miR-31 and adding heparin-binding EGF-like growth factor (HBEGF).

scholarly journals Reactive Oxygen Species and Nrf2: Functional and Transcriptional Regulators of Hematopoiesis

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Linping Hu ◽  
Yawen Zhang ◽  
Weimin Miao ◽  
Tao Cheng
Keyword(s):  
Reactive Oxygen Species ◽  
Oxygen Sensor ◽  
Hypoxia Inducible Factor ◽  
Reactive Oxygen ◽  
Ambient Air ◽  
Oxygen Species ◽  
Human Cord Blood ◽  
Hematopoietic Stem ◽  
Hypoxia Inducible Factor 1 ◽  
Cellular Oxygen

Hematopoietic stem cells (HSCs) are characterized by self-renewal and multilineage differentiation potentials. Although they play a central role in hematopoietic homeostasis and bone marrow (BM) transplantation, they are affected by multiple environmental factors in the BM. Here, we review the effects of reactive oxygen species (ROS) and Nrf2 on HSC function and BM transplantation. HSCs reside in the hypoxic microenvironment of BM, and ROS play an important role in HSPC regulation. Recently, an extraphysiologic oxygen shock/stress phenomenon was identified in human cord blood HSCs collected under ambient air conditions. Moreover, Nrf2 has been recently recognized as a master transcriptional factor that regulates multiple antioxidant enzymes. Since several years, the role of Nrf2 in hematopoiesis has been extensively studied, which has functional similarities of cellular oxygen sensor hypoxia-inducible factor-1 as transcriptional factors. Increasing evidence has revealed that abnormally elevated ROS production due to factors such as genetic defects, aging, and ionizing radiation unexceptionally resulted in lethal impairment of HSC function and hematopoiesis. Both experimental and clinical studies have identified elevated ROS levels as a major culprit of ineffective BM transplantation. Lastly, we discuss the possibility of using small molecule antioxidants, such as N-acetyl cysteine, resveratrol, and curcumin, to augment HSC function and improve the therapeutic efficacy of BM transplantation. Further research on the function of ROS levels and improving the efficacy of BM transplantation may have a great potential for broad clinical applications of HSCs.

scholarly journals 55th Bowditch Lecture: Effects of chronic hypoxia on the pulmonary circulation: Role of HIF-1

2012 ◽  
Vol 113 (9) ◽  
pp. 1343-1352 ◽  
Author(s):  
Larissa A. Shimoda
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Circulation ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1 ◽  
Pulmonary Arterial ◽  
Expression And Activity

When exposed to chronic hypoxia (CH), the pulmonary circulation responds with enhanced contraction and vascular remodeling, resulting in elevated pulmonary arterial pressures. Our work has identified CH-induced alterations in the expression and activity of several ion channels and transporters in pulmonary vascular smooth muscle that contribute to the development of hypoxic pulmonary hypertension and uncovered a critical role for the transcription factor hypoxia-inducible factor-1 (HIF-1) in mediating these responses. Current work is focused on the regulation of HIF in the chronically hypoxic lung and evaluation of the potential for pharmacological inhibitors of HIF to prevent, reverse, or slow the progression of pulmonary hypertension.

scholarly journals Nitric Oxide Modulates Oxygen Sensing by Hypoxia-inducible Factor 1-dependent Induction of Prolyl Hydroxylase 2

2006 ◽  
Vol 282 (3) ◽  
pp. 1788-1796 ◽  
Author(s):  
Utta Berchner-Pfannschmidt ◽  
Hatice Yamac ◽  
Buena Trinidad ◽  
Joachim Fandrey
Keyword(s):  
Nitric Oxide ◽  
Oxygen Sensing ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Hypoxia Inducible Factor 1

Hypoxia-Inducible Factor-1 in Multiple Myeloma Progression.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1812-1812
Author(s):  
Roberto Ria ◽  
Antonia Reale ◽  
Simona Berardi ◽  
Claudia Piccoli ◽  
Giulia Di Pietro ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Endothelial Cells ◽  
Target Genes ◽  
Plasma Cells ◽  
Hypoxia Inducible Factor ◽  
Immunofluorescent Staining ◽  
Enzyme Linked Immunosorbent Assay ◽  
Vegf Receptor ◽  
Rt Pcr ◽  
Hypoxia Inducible Factor 1

Abstract Abstract 1812 Poster Board I-838 Multiple Myeloma (MM) is a malignancy of immunoglobulin (Ig)-synthesizing plasma cells, that home to and expand in the bone marrow. Similarly to other tumours its development is correlated to the formation of regions of hypoxia, which may be a prognostic indicator and determinant of malignant progression. It is known how in solid tumours the degree of intra-tumoral hypoxia is positively correlated with the expression of the transcription factor hypoxia-inducible factor 1 (HIF-1). HIF-1 is composed of HIF-1á and HIF-1β subunits and its production has been identified as a key element in allowing cells to adapt and survive in a hostile hypoxic environment via a variety of pathways. In hypoxia conditions, the HIF-1á subunit becomes stable and regulates the expression of target genes. When activated HIF-1á also targets those genes which are required for angiogenesis, the development of new blood vessels from an existing vascular network. Angiogenesis represents a constant hallmark of MM progression. In response to hypoxia plasma cells and stromal cells (endothelial cells [ECs], macrophages, mast cells) within the tumour express Vascular Endothelial Growth Factor (VEGF), a mitogen and survival factor specific for endothelial cells. VEGF is the major regulator of tumor-associated angiogenesis. HIF-1á directly activates transcription of the VEGF gene and this leads to autocrine signal transduction that is critical for angiogenesis. In this study we demonstrate the role of HIF-1á in MM angiogenesis. The constitutive stabilization of HIF-1á contributes to increase angiogenesis in MM. Our data show that HIF-1á is stabilized in the nucleus of MM endothelial cells (MMECs) but not in ECs of Monoclonal Gammopathies of Undetermined Significance (MGECs) and in Human Umbilical Vein ECs (HUVECs) used as controls. Western Blot and Enzyme-Linked Immunosorbent Assay (ELISA) analyses show the overexpression of HIF-1á and the proteic products of its target genes VEGF and VEGF Receptor (VEGFR)-1, in patients with relapsed disease and in MM progression but not in patients with nonactive MM (avascular phase). Moreover, immunofluorescent staining confirm the nuclear stabilization of HIF-1á in MMECs. At mRNA level all ECs express same quantity of HIF-1á mRNA, as confirmed by RT-PCR and Real-time RT-PCR, indicating that in MMECs the post-trascriptional control is affected. Finally, we show that the inhibition of HIF-1á by siRNA suppresses vessel formation in vitro and promote ECs apoptosis. Our findings indicate that HIF-1á plays an important role in MM progression and that it is correlated to the angiogenic switch from nonactive MM to active MM. Furthermore these data suggest that HIF-1á may represent a target for the MM antiangiogenic treatment. Disclosures No relevant conflicts of interest to declare.

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