Comparative study of the distribution and expression of Neuroglobin and Hypoxia-inducible factor-1α in the adult and young Yak Brain.
Brazilian journal of biology = Revista brasleira de biologia
BACKGROUND:The brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. AIM:The study examined the expression of Neuroglobin (Ngb) and Hypoxia-inducible factor-1α (Hif-1α) in adult and young yak brain tissues, and provided researchers with meaningful insight into the anatomy, physiology, and biochemistry of this mammal. METHOD:The study employed immunohistochemistry (IHC), quantitative real-time PCR (qRT-PCR), and Western blot (WB) to obtain the results. RESULTS:Ngb and Hif-1α were significantly (P<0.05) expressed in the cerebellar cortex, piriform lobe, medulla, and corpus callosum of the adult yak while in the young yak brain tissues, the protein expressions were significantly found in the white matter of the cerebellum, pineal gland, corpus callosum, and cerebellar cortex. The Ngb and Hif-1α expression showed similarities and differences. This may have resulted from similar animal species, source of nutrition, age factors, brain size, emotional activities, and communication. The findings documented that Ngb and Hif-1α are commonly expressed in various adult and young yak brain tissues. Multiple roles in the brain tissues of the adult and young yaks are involved in the expression and distribution and are proposed to play a significant role in the adaptation of the yak to the high altitude environment. CONCLUSION:This study provides meaningful data to understand the adaptive mechanism to hypoxia and recommended researchers to expand on the adaptive mechanism and brain tissues that are not recorded.
10.1590/1519-6984.245330
Hypoxic stress upregulates K2.1 expression by a pathway including hypoxic-inducible factor-1α and dynamin2 in brain capillary endothelial cells.
Yamamura Hideto,Suzuki Yoshiaki,Yamamura Hisao,Asai Kiyofumi,Giles Wayne,Imaizumi Yuji
American journal of physiology. Cell physiology
Brain capillary endothelial cells (BCECs) play a central role in maintenance of blood-brain barrier (BBB) function and, therefore, are essential for central nervous system homeostasis and integrity. Although brain ischemia damages BCECs and causes disruption of BBB, the related influence of hypoxia on BCECs is not well understood. Hypoxic stress can upregulate functional expression of specific K currents in endothelial cells, e.g., K2.1 channels without any alterations in the mRNA level, in t-BBEC117, a cell line derived from bovine BCECs. The hyperpolarization of membrane potential due to K2.1 channel upregulation significantly facilitates cell proliferation. In the present study, the mechanisms underlying the hypoxia-induced K2.1 upregulation was examined. We emphasize the involvement of dynamin2, a protein known to be involved in a number of surface expression pathways. Hypoxic culture upregulated dynamin2 expression in t-BBEC117 cells. The inhibition of dynamin2 by Dynasore canceled hypoxia-induced upregulation of K2.1 currents by reducing surface expression. On the contrary, K2.1 currents and proteins in t-BBEC117 cultured under normoxia were increased by overexpression of dynamin2, but not by dominant-negative dynamin2. Molecular imaging based on bimolecular fluorescence complementation, double-immunostaining, and coimmunoprecipitation assays revealed that dynamin2 can directly bind to the K2.1 channel. Moreover, hypoxic culture downregulated hypoxic-inducible factor-1α (HIF-1α) expression. Knockdown of HIF-1α increased dynamin2 expression in t-BBEC117 cells, in both normoxic and hypoxic culture conditions. In summary, our results demonstrated that hypoxia downregulates HIF-1α, increases dynamin2 expression, and facilitates K2.1 surface expression, resulting in hyperpolarization of membrane potential and subsequent increase in Ca influx in BCECs.
10.1152/ajpcell.00154.2017
Effects of Altitude and Duration of Differing Levels of Hypoxic Exposure on Hypoxia-Inducible Factor-1α in Rat Tissues.
High altitude medicine & biology
Li, Xiao-lin, Wei-gang Wang, Mao-xing Li, Tian-long Liu, Xiu-yu Tian, and Lan Wu. Effects of altitude and duration of differing levels of hypoxic exposure on hypoxia-inducible factor-1α in rat tissues. . 23:173-184, 2022. This research aimed to evaluate the effects of hypoxia at different altitudes and durations on the expression of hypoxia-inducible factor-1α (HIF-1α) in rat tissues. A total of 72 Wistar rats were used to investigate the effect of hypoxia at different durations on rat tissues and 72 Wistar rats were used to investigate the effect of hypoxia at different altitudes. Hematoxylin and Eosin (HE) staining was performed to observe the pathological changes of hippocampus tissues, and the expression of HIF-1α of rats under conditions of hypoxia was detected by quantitative real-time polymerase chain reaction and western blotting. According to the pathological results, we found that the degree of the brain, lung, and heart damage and HIF-1α expression, showed an increasing trend as the altitude (1,500, 3,000, 4,500, 6,000, 7,500, and 8,000 m for 12 hours) and duration (0, 6, 12, 24, 36, and 72 hours at 7,500 m) of hypoxia increased. Although there is a significant difference at 8,000 m, considering model stability, animal ethics and cost, we chose 7,500 m as a fixed altitude during hypoxia at different durations. Compared with the normoxic group, the expression of HIF-1α mRNA in the 7,500 m significantly increased by 30.48%, 21.00%, and 12.62%, in brain, lung, and heart tissue ( < 0.01), and HIF-1α mRNA in the 72-hour hypoxic exposure group significantly increased by 52.58%, 20.39%, 27.88% in tissues ( < 0.05). Compared with the normoxic group, HIF-1α protein expressions in the 7,500 m significantly increased by 10.26%, 31.71%, and 13.33% in brain, lung, and heart tissue ( < 0.01, < 0.01, < 0.05), and HIF-1α protein expressions in the 72-hour hypoxic exposure group significantly increased by 18.89%, 22.89%, and 29.75% in tissues ( < 0.05). HIF-1α expression in the rat was correlated with altitude and duration of hypoxic exposure.
10.1089/ham.2021.0100
Blood redistribution preferentially protects vital organs under hypoxic stress in Pelteobagrus vachelli.
Aquatic toxicology (Amsterdam, Netherlands)
Blood redistribution occurs in mammals under hypoxia but has not been reported in fish. This study investigated the tissue damage, hypoxia-inducible factor (HIF) activation level, and blood flow changes in the brain, liver, and muscle of Pelteobagrus vachelli during the hypoxia process for normoxia-hypoxia-asphyxia. The results showed that P. vachelli has tissue specificity in response to hypoxic stress. Cerebral blood flow increased with less damage than in the liver and muscle, suggesting that P. vachelli may also have a blood redistribution mechanism in response to hypoxia. It is worth noting that severe hypoxia can lead to a sudden increase in the degree of brain tissue damage. In addition, higher dissolved oxygen levels activate HIF and may have contributed to the reduced damage observed in the brain. This study provides basic data for investigating hypoxic stress in fish.
10.1016/j.aquatox.2023.106498
In chronic hypoxia, glucose availability and hypoxic severity dictate the balance between HIF-1 and HIF-2 in astrocytes.
Guo Min,Ma Xiaoye,Feng Yiwei,Han Sida,Dong Qiang,Cui Mei,Zhao Yanxin
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Astrocyte function is an important contributor to cellular viability during brain hypoxia and ischemia. Levels of the hypoxia-inducible transcription factors (HIFs) HIF-1 and HIF-2 are increased in hypoxic conditions and impact the neuroprotective properties of astrocytes. For example, HIF-2 induces levels of erythropoietin (EPO), a neuroprotectant, by astrocytes. In contrast, HIF-1 activity in astrocytes diminishes the viability of neurons in cocultures during hypoxia. Thus, HIF-1 and HIF-2 may have opposing effects on astrocytes. In this study, we explore the balance of HIF-1 and HIF-2 signaling in astrocytes during chronic (1-7 d) hypoxia while altering the degree of hypoxia and glucose availability. In addition, we investigate the effects of these conditions on neuron apoptosis. During exposure to chronic moderate hypoxia (2% O) and plentiful glucose (10 mM), HIF-2 and EPO abundance increases from d 1 to 7. Similarly, pretreatment with moderate hypoxia markedly increases the abundance of HIF-2 and EPO when astrocytes are subsequently exposed to severe hypoxia (0.5% O; 24 h) in 10 mM glucose, which inhibits neuron apoptosis in coculture. Although HIF-1 targets the expression increase during the 7 d in chronic moderate hypoxia (2% O) and limited glucose (2 mM), further exposure to severe hypoxia (0.5% O; 24 h) induces a decrease of most HIF-1 targets in astrocytes. Notably, in astrocyte exposure to 2% O prior to 0.5% O, the expression of iNOS, an HIF-1-regulated protein, keeps increasing when glucose is limited, whereas EPO and VEGF abundance is suppressed, inducing increased apoptosis of neurons in coculture under limited glucose (2 mM). Thus, both hypoxic severity and glucose abundance regulate the balance of HIF-1 and HIF-2 activity in astrocytes, leading to diverse effects on neurons. These results could have important implications on the adaptive or pathologic role of astrocytes during chronic hypoxia and ischemia.-Guo, M., Ma, X., Feng, Y., Han, S., Dong, Q., Cui, M., Zhao, Y. In chronic hypoxia, glucose availability and hypoxic severity dictate the balance between HIF-1 and HIF-2 in astrocytes.
10.1096/fj.201900402RR
Comparative study on the distribution and expression of Neuroglobin and Hypoxia-inducible factor-1α in the telencephalon of yak and cattle.
Brazilian journal of biology = Revista brasleira de biologia
The telencephalon refers to the most highly developed and anterior part of the forebrain, consisting mainly of the cerebral hemispheres. The study determined Neuroglobin (Ngb) and Hypoxia-inducible factor (HIF-1α) expression in the telencephalon of yak and cattle, and compare the expression and distribution pattern of Ngb and HIF-1α in the two animals. Immunohistochemistry (IHC), quantitative real-time Polymerase Chain Reaction (qRT-PCR), and Western blot (WB) were employed to investigate Ngb and Hif-1α expression in the telencephalon of yak and cattle. mRNA and protein expressions of Ngb and HIF-1α showed positive in different tissues of the yak and cattle telencephalon. Ngb expression in tissues of the yak recorded higher as compare to cattle while HIF-1α expression was found higher in cattle than yak. The HIF-1α expression in some tissues of yak telencephalon was consistent with the cattle. The results documented that HIF-1α may have a direct or indirect synergistic effect on Ngb expression in the yak telencephalon to improve hypoxia adaptation. It is suggested that yak may need more Ngb expression for adaptation, but the expression of HIF-1α seems to be down-regulated during long-term adaptation, and the specific causes of this phenomenon needs to be further verified.
10.1590/1519-6984.248911
Brain adaptation to hypoxia and hyperoxia in mice.
Terraneo Laura,Paroni Rita,Bianciardi Paola,Giallongo Toniella,Carelli Stephana,Gorio Alfredo,Samaja Michele
Redox biology
AIMS:Hyperoxic breathing might lead to redox imbalance and signaling changes that affect cerebral function. Paradoxically, hypoxic breathing is also believed to cause oxidative stress. Our aim is to dissect the cerebral tissue responses to altered O fractions in breathed air by assessing the redox imbalance and the recruitment of the hypoxia signaling pathways. RESULTS:Mice were exposed to mild hypoxia (10%O), normoxia (21%O) or mild hyperoxia (30%O) for 28 days, sacrificed and brain tissue excised and analyzed. Although one might expect linear responses to %O, only few of the examined variables exhibited this pattern, including neuroprotective phospho- protein kinase B and the erythropoietin receptor. The major reactive oxygen species (ROS) source in brain, NADPH oxidase subunit 4 increased in hypoxia but not in hyperoxia, whereas neither affected nuclear factor (erythroid-derived 2)-like 2, a transcription factor that regulates the expression of antioxidant proteins. As a result of the delicate equilibrium between ROS generation and antioxidant defense, neuron apoptosis and cerebral tissue hydroperoxides increased in both 10%O and 30%O, as compared with 21%O. Remarkably, the expression level of hypoxia-inducible factor (HIF)-2α (but not HIF-1α) was higher in both 10%O and 30%O with respect to 21%O INNOVATION: Comparing the in vivo effects driven by mild hypoxia with those driven by mild hyperoxia helps addressing whether clinically relevant situations of O excess and scarcity are toxic for the organism. CONCLUSION:Prolonged mild hyperoxia leads to persistent cerebral damage, comparable to that inferred by prolonged mild hypoxia. The underlying mechanism appears related to a model whereby the imbalance between ROS generation and anti-ROS defense is similar, but occurs at higher levels in hypoxia than in hyperoxia.
10.1016/j.redox.2016.10.018
Expression and distribution of neuroglobin and hypoxia-inducible factor-1α in the adult yak telencephalon.
Veterinary medicine and science
The telencephalon is also known as the cerebrum, and it consists of the largest part of the brain. It makes up about 85% of the total weight of the brain. Neuroglobin (Ngb) is a protein found in neurons of both the peripheral and central nervous system that appears to convey some resilience to hypoxia, while the hypoxia-inducible factor (Hif-1α) is a dimeric protein complex that plays an integral role in the body's response to low oxygen concentrations, or hypoxia. The study examines the expression of Ngb and Hif-1α in the telencephalon of adult yak in the telencephalon. The immunohistochemistry (IHC), quantitative real-time PCR and Western blot (WB) were employed to investigate Ngb and Hif-1α expression in the telencephalon. Ngb and Hif-1α are significantly expressed in all tissues of the telencephalon except the hypothalamus. The cerebellar cortex, hippocampus, amygdala, cerebellum and corpus callosum recorded the highest expression but not significant. The overall expression revealed that Ngb expression was higher as compared to Hif-1α. The IHC results also showed that the expression of Ngb and Hif-1α were higher in the cerebellar cortex, hippocampus, amygdala, cerebellum and corpus callosum as compared to other regions. The results suggested that Ngb and Hif-1α expression influence the adaptive mechanism of yak to the high altitude environment. Both Ngb and Hif-1α participate in oxygen transports throughout the telencephalon and have functions in neuroprotection. Further studies are needed to confirm the mechanism of adaptation.
10.1002/vms3.553
F-box and WD repeat domain-containing 7 (FBXW7) mediates the hypoxia inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) signaling pathway to affect hypoxic-ischemic brain damage in neonatal rats.
Sun Ling
Bioengineered
The aim of this study was to determine whether F-box and WD repeat domain-containing 7 (FBXW7) can mediate the hypoxia inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) signaling pathway to affect neonatal hypoxic-ischemic brain damage (HIBD) in neonatal rats. HIBD rats were treated with LV-shFBXW7. Cerebral infarct size was determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining, while microvessel density (MVD) was evaluated by immunohistochemistry. Learning and memory were tested using the Morris water maze (MWM) test. FBXW7 and HIF-1α/VEGF signaling pathway proteins were measured by Western blotting. Brain microvascular endothelial cells (BMECs) were isolated to establish an oxygen-glucose deprivation (OGD) model to evaluate treatment with FBXW7 siRNA. Cell viability was detected using a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, while cell migration was evaluated using a wound healing assay. The tube formation of BMECs was also assessed. The results demonstrated that HIBD rats exhibited increased protein expression of FBXW7, HIF-1α, and VEGF. HIBD rats also displayed increased cerebral infarct size, prolonged escape latency and a decreased number of platform crossings. However, HIBD rats treated with LV-shFBXW7 exhibited reversal of these changes. experiments showed that BMECs in the OGD group had significantly decreased cell viability, shorter vascular lumen length, and shorter migration distance than cells in the control group. Moreover, silencing FBXW7 promoted proliferation, tube formation and migration of BMECs. Taken together, silencing FBXW7 upregulates the HIF-1α/VEGF signaling pathway to promote the angiogenesis of neonatal HIBD rats after brain injury, reducing infarct volume and improving recovery of nerve function in HIBD rats.
10.1080/21655979.2021.2011635
Comparative Study of HIF-1α- and HIF-2α-Immunopositive Neurons and Capillaries in Rat Cortex under Conditions of Tissue Hypoxia.
Chertok V M,Nevzorova V A,Zakharchuk N V
Bulletin of experimental biology and medicine
We measured the content of HIF-1α and HIF-2α-immunopositive neurons and microvessels in the brain of Wistar rats during the first 24 h of tissue hypoxia induced by subcutaneous injection of cobalt dichloride (50 mg/kg). In control rats (without hypoxia), immunohistochemical marker HIF-2α in cortex of parietal lobe was not detected, and HIF-1α was detected only in few weakly stained pale neurons and capillaries. In 30 min after injection of the cobalt salt, the number of HIF-1α neurons increased by 25.6% (in capillaries by 12.3%), many of these were characterized by intensive reaction; the quantitative parameters reached their maximum level within 1-3 h. However, the concentration of immunopositive neurons returned to the control values in 6 h after hypoxia modeling (capillaries in 9 h). In contrast to HIF-1α, the number of neurons and capillaries containing HIF-2α reached a maximum level in 6-12 h of hypoxia. The relative density of HIF-2α capillaries increased most pronouncedly (by 23.6%); the relative density of neurons increased by 18.9%. The relative density of HIF-2α cells did not change significantly to the end of the experiment. Thus, HIF-1α is more essential for regulation of adaptation to hypoxia in neurons and HIF-2α is more important for the endothelium of microvessels.
10.1007/s10517-018-4207-6
The Potential Role of Hypoxia-Inducible Factor-1 in the Progression and Therapy of Central Nervous System Diseases.
Current neuropharmacology
Hypoxia-inducible factor-1 (HIF-1) is a heterodimer protein composed of an oxygenregulated functional subunit, HIF-1α, and a structural subunit, HIF-1β, belonging to the basic helixloop- helix family. Strict regulation of HIF-1 protein stability and subsequent transcriptional activity involves various molecular interactions and is primarily controlled by post-transcriptional modifications. Hypoxia, owing to impaired cerebral blood flow, has been implicated in a range of central nervous system (CNS) diseases by exerting a deleterious effect on brain function. As a master oxygen- sensitive transcription regulator, HIF-1 is responsible for upregulating a wide spectrum of target genes involved in glucose metabolism, angiogenesis, and erythropoiesis to generate the adaptive response to avoid, or at least minimize, hypoxic brain injury. However, prolonged, severe oxygen deprivation may directly contribute to the role-conversion of HIF-1, namely, from neuroprotection to the promotion of cell death. Currently, an increasing number of studies support the fact HIF-1 is involved in a variety of CNS-related diseases, such as intracranial atherosclerosis, stroke, and neurodegenerative diseases. This review article chiefly focuses on the effect of HIF-1 on the pathogenesis and mechanism of progression of numerous CNS-related disorders by mediating the expression of various downstream genes and extensive biological functional events and presents robust evidence that HIF-1 may represent a potential therapeutic target for CNS-related diseases.
10.2174/1570159X19666210729123137
Pericyte, but not astrocyte, hypoxia inducible factor-1 (HIF-1) drives hypoxia-induced vascular permeability in vivo.
Baumann Julia,Tsao Chih-Chieh,Patkar Shalmali,Huang Sheng-Fu,Francia Simona,Magnussen Synnøve Norvoll,Gassmann Max,Vogel Johannes,Köster-Hegmann Christina,Ogunshola Omolara O
Fluids and barriers of the CNS
BACKGROUND:Ways to prevent disease-induced vascular modifications that accelerate brain damage remain largely elusive. Improved understanding of perivascular cell signalling could provide unparalleled insight as these cells impact vascular stability and functionality of the neurovascular unit as a whole. Identifying key drivers of astrocyte and pericyte responses that modify cell-cell interactions and crosstalk during injury is key. At the cellular level, injury-induced outcomes are closely entwined with activation of the hypoxia-inducible factor-1 (HIF-1) pathway. Studies clearly suggest that endothelial HIF-1 signalling increases blood-brain barrier permeability but the influence of perivascular HIF-1 induction on outcome is unknown. Using novel mouse lines with astrocyte and pericyte targeted HIF-1 loss of function, we herein show that vascular stability in vivo is differentially impacted by perivascular hypoxia-induced HIF-1 stabilization. METHODS:To facilitate HIF-1 deletion in adult mice without developmental complications, novel Cre-inducible astrocyte-targeted (GFAP-CreER; HIF-1α and GLAST-CreER; HIF-1α) and pericyte-targeted (SMMHC-CreER; HIF-1α) transgenic animals were generated. Mice in their home cages were exposed to either normoxia (21% O) or hypoxia (8% O) for 96 h in an oxygen-controlled humidified glove box. All lines were similarly responsive to hypoxic challenge and post-Cre activation showed significantly reduced HIF-1 target gene levels in the individual cells as predicted. RESULTS:Unexpectedly, hypoxia-induced vascular remodelling was unaffected by HIF-1 loss of function in the two astrocyte lines but effectively blocked in the pericyte line. In correlation, hypoxia-induced barrier permeability and water accumulation were abrogated only in pericyte targeted HIF-1 loss of function mice. In contrast to expectation, brain and serum levels of hypoxia-induced VEGF, TGF-β and MMPs (genes known to mediate vascular remodelling) were unaffected by HIF-1 deletion in all lines. However, in agreement with the permeability data, immunofluorescence and electron microscopy showed clear prevention of hypoxia-induced tight junction disruption in the pericyte loss of function line. CONCLUSION:This study shows that pericyte but not astrocyte HIF-1 stabilization modulates endothelial tight junction functionality and thereby plays a pivotal role in hypoxia-induced vascular dysfunction. Whether the cells respond similarly or differentially to other injury stimuli will be of significant relevance.
10.1186/s12987-021-00302-y
HIF-1α is involved in blood-brain barrier dysfunction and paracellular migration of bacteria in pneumococcal meningitis.
Acta neuropathologica
Bacterial meningitis is a deadly disease most commonly caused by Streptococcus pneumoniae, leading to severe neurological sequelae including cerebral edema, seizures, stroke, and mortality when untreated. Meningitis is initiated by the transfer of S. pneumoniae from blood to the brain across the blood-cerebrospinal fluid barrier or the blood-brain barrier (BBB). The underlying mechanisms are still poorly understood. Current treatment strategies include adjuvant dexamethasone for inflammation and cerebral edema, followed by antibiotics. The success of dexamethasone is however inconclusive, necessitating new therapies for controlling edema, the primary reason for neurological complications. Since we have previously shown a general activation of hypoxia inducible factor (HIF-1α) in bacterial infections, we hypothesized that HIF-1α, via induction of vascular endothelial growth factor (VEGF) is involved in transmigration of pathogens across the BBB. In human, murine meningitis brain samples, HIF-1α activation was observed by immunohistochemistry. S. pneumoniae infection in brain endothelial cells (EC) resulted in in vitro upregulation of HIF-1α/VEGF (Western blotting/qRT-PCR) associated with increased paracellular permeability (fluorometry, impedance measurements). This was supported by bacterial localization at cell-cell junctions in vitro and in vivo in brain ECs from mouse and humans (confocal, super-resolution, electron microscopy, live-cell imaging). Hematogenously infected mice showed increased permeability, S. pneumoniae deposition in the brain, along with upregulation of genes in the HIF-1α/VEGF pathway (RNA sequencing of brain microvessels). Inhibition of HIF-1α with echinomycin, siRNA in bEnd5 cells or using primary brain ECs from HIF-1α knock-out mice revealed reduced endothelial permeability and transmigration of S. pneumoniae. Therapeutic rescue using the HIF-1α inhibitor echinomycin resulted in increased survival and improvement of BBB function in S. pneumoniae-infected mice. We thus demonstrate paracellular migration of bacteria across BBB and a critical role for HIF-1α/VEGF therein and hence propose targeting this pathway to prevent BBB dysfunction and ensuing brain damage in infections.
10.1007/s00401-020-02174-2
Different Expressions of HIF-1α and Metabolism in Brain and Major Visceral Organs of Acute Hypoxic Mice.
International journal of molecular sciences
Hypoxia is associated with clinical diseases. Extreme hypoxia leads to multiple organs failure. However, the different effects of hypoxia on brain and visceral organs still need to be clarified, and moreover, characteristics in vulnerable organs suffering from hypoxia remain elusive. In the present study, we first aimed to figure out the hypoxic sensitivity of organs. Adult male mice were exposed to 6% O or 8% O for 6 h. Control mice were raised under normoxic conditions. In vivo and in vitro imaging of anti-HIF-1α-NMs-cy5.5 nanocomposites showed that the expression level of hypoxia-inducible factor (HIF-1α) was the highest in the liver, followed by kidney and brain. HIF-1α was detected in the hepatocytes of liver, distal convoluted tubules of kidney and neurons of cerebral cortex. The liver, kidney and brain showed distinct metabolic profiles but an identical change in glutamate. Compared with kidney and brain, the liver had more characteristic metabolites and more disturbed metabolic pathways related to glutaminolysis and glycolysis. The level of O-phosphocholine, GTP, NAD and aspartate were upregulated in hypoxic mice brain, which displayed significant positive correlations with the locomotor activity in control mice, but not in hypoxic mice with impaired locomotor activities. Taken together, the liver, kidney and brain are the three main organs of the body that are strongly respond to acute hypoxia, and the liver exhibited the highest hypoxic sensitivity. The metabolic disorders appear to underlie the physiological function changes.
10.3390/ijms22136705
HIF-1 regulates energy metabolism of the Tibetan chicken brain during embryo development under hypoxia.
Tang Qiguo,Xu Qinqin,Ding Cui,Zhang Hao,Ling Yao,Wu Changxin,Fang Meiying
American journal of physiology. Regulatory, integrative and comparative physiology
The Tibetan chicken (; TBC) is an indigenous breed found in the Qinghai-Tibet Plateau that are well adapted to a hypoxic environment. The energy metabolism of embryonic brains in TBCs under hypoxia has been little reported. This study investigated changes in energy metabolism of the TBC brain during embryo development under hypoxia. We found that TBCs exhibited a change of glycolysis and the tricarboxylic acid cycle during embryo development under hypoxia. Hypoxia-inducible factor (HIF)-1 was potentially involved in this by directly inducing overexpression of pyruvate dehydrogenase kinase 1 () and the glycolytic genes hexokinase 1 () and lactate dehydrogenase A () to increase glycolysis of TBCs to adapt to hypoxia. Although these may not be unique to TBCs, as we had also found similar results in Dwarf Laying Chickens, a lowland chicken breed, TBCs had a stronger regulating ability. In summary, our study revealed that HIF-1 induced energy metabolism changes in the TBC brain via upregulating expressions of PDK1 and other HIF-1 target genes like HK1 and LDHA to increase glycolysis for TBC hypoxic adaptations during embryo development. It indicates the potential application of TBC energy metabolism research for other animals living on the Qinghai-Tibet Plateau.
10.1152/ajpregu.00052.2020
Effects of Hypoxia-Inducible Factor 1 (HIF-1) Signaling Pathway on Acute Ischemic Stroke.
Computational and mathematical methods in medicine
Background:Epidemiological surveys show that a large number of cerebrovascular diseases occur in China every year, and among these cerebrovascular diseases, ischemic diseases are predominant. Ischemia leads to irreversible degenerative necrosis of a large number of brain neurons and severe neurological deficits. Aims:This study is aimed at exploring the mechanism of the major regulatory effect of hypoxia-inducible factor 1 (HIF-1) pathway on proangiogenesis and providing new ideas for the treatment of ischemic stroke. Materials and Methods:The rats were randomly divided into normal and ischemic control groups, and the ischemic control group was subjected to the middle cerebral artery occlusion (MCAO) cerebral ischemia model by the wire embolization method, and the rats were executed in batches at 6 h, 1 d, and 3 d after ischemia-reperfusion, and the brain tissue specimens were taken for examination to investigate the effect of hypoxia-inducible factor 1 (HIF-l) signaling pathway on acute ischemic stroke. Results:At 3 d, the number of VEGFR2 positive cells increased significantly, and there was a significant difference compared with the control group ( < 0.05). At 3 d, the number of HIF-1-positive cells increased significantly, and there was a significant difference compared with the control group ( < 0.05). The number of Hes1+factor VIII positive cells in the ischemic cortex increased significantly on the 1st and 3rd day, and there was a significant difference compared with the control group ( < 0.05). The expression of Hes1 protein was significantly lower than the normal level after 6 h of ischemia, and the protein expression was significantly increased at 1 d and 3 d after ischemia ( < 0.05). Conclusion:By detecting the expression changes of Hesl+factor VII in the ischemic area, the results show that ischemia and hypoxia activate the HIF-1, making the HIF-l the main regulatory pathway in the process of angiogenesis after ischemia.
10.1155/2022/1860925
Metabolic Regulation of Hypoxia-Inducible Factors in Hypothalamus.
Du Dan,Zhang Yugang,Zhu Canjun,Chen Hong,Sun Jia
Frontiers in endocrinology
The earliest hypoxia-inducible factor (HIF) function was to respond to hypoxia or hypoxic conditions as a transcription factor. Recent studies have expanded our understanding of HIF, and a large amount of evidence indicates that HIF has an essential effect on central regulation of metabolism. The central nervous system's response to glucose, inflammation, and hormones' main influence on systemic metabolism are all regulated by HIF to varying degrees. In the hypothalamus, HIF mostly plays a role in inhibiting energy uptake and promoting energy expenditure, which depends not only on the single effect of HIF or a single part of the hypothalamus. In this paper, we summarize the recent progress in the central regulation of metabolism, describe in detail the role of HIF in various functions of the hypothalamus and related molecular mechanisms, and reveal that HIF is deeply involved in hypothalamic-mediated metabolic regulation.
10.3389/fendo.2021.650284
HIF-1α and VEGF Are Involved in Deferoxamine-Ameliorated Traumatic Brain Injury.
Wang Kai,Jing Yao,Xu Chen,Zhao Jianwei,Gong Qiuyuan,Chen Shiwen
The Journal of surgical research
BACKGROUND:Deferoxamine (DFX) has been reported to have neuroprotective effect. This study aimed to investigate the neuroprotective effect of DFX and its effect on hypoxia-inducible factor 1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) in rats after traumatic brain injury (TBI). MATERIALS AND METHODS:Rats were randomly divided into sham operation, TBI + DFX, and TBI + vehicle groups. The rats in the TBI + DFX group were intraperitoneally injected with DFX 2 and 6 h after injury, thereafter once every 12 h. The rats in the TBI + vehicle group were intraperitoneally injected with saline at the same time points. At 6, 12, 24, and 48 h after TBI, 6 rats in each group were euthanized, and the brains were harvested. The expression of HIF-1α and VEGF in the pericontusional area was detected using real-time polymerase chain reaction and Western blot analysis. TBI-induced apoptosis was investigated using the TdT-mediated dUTP nick-end labeling (TUNEL) method. Three days after TBI, the density of microvessels was examined via immunohistochemical staining. RESULTS:DFX treatment upregulated the expression of HIF-1α and VEGF after TBI. DFX treatment reduced apoptosis and improved the neurobehavioral score after TBI. The density of microvessels was higher in the TBI + DFX group than that in the TBI + vehicle group 3 d after TBI. CONCLUSIONS:DFX can stimulate angiogenesis, inhibit apoptosis, and play a protective role after TBI. The protective effect of DFX may, at least in part, be through upregulating the expression of HIF-1α and its downstream target gene VEGF.
10.1016/j.jss.2019.09.023
HIF‑1α in cerebral ischemia (Review).
Dong Peiliang,Li Qingna,Han Hua
Molecular medicine reports
Cerebral ischemic injury may lead to a series of serious brain diseases, death or different degrees of disability. Hypoxia‑inducible factor‑1α (HIF‑1α) is an oxygen‑sensitive transcription factor, which mediates the adaptive metabolic response to hypoxia and serves a key role in cerebral ischemia. HIF‑1α is the main molecule that responds to hypoxia. HIF‑1α serves an important role in the development of cerebral ischemia by participating in numerous processes, including metabolism, proliferation and angiogenesis. The present review focuses on the endogenous protective mechanism of cerebral ischemia and elaborates on the role of HIF‑1α in cerebral ischemia. In addition, it focuses on cerebral ischemia interventions that act on the HIF‑1α target, including biological factors, non‑coding RNA, hypoxic‑ischemic preconditioning and drugs, and expands upon the measures to strengthen the endogenous compensatory response to support HIF‑1α as a therapeutic target, thus providing novel suggestions for the treatment of cerebral ischemia.
10.3892/mmr.2021.12557
Cerebral Mechanisms of Hypoxic/Ischemic Postconditioning.
Vetrovoy O V,Rybnikova E A,Samoilov M O
Biochemistry. Biokhimiia
This review analyzes recent data on mechanisms of cerebral hypoxia and the protective methods of hypoxic and ischemic postconditioning, as well as their interrelationship with the key mechanisms responsible for neuroprotection and neuroplasticity. Upregulation of expression of antiapoptotic factors and neurotrophins and modulation of activity of several protein kinases and transcription factors such as hypoxia-inducible factor-1 (HIF-1) are considered as the most important aspects in the neuroprotective potential of postconditioning. The presented information indicates substantial transformative promise of the noninvasive techniques of hypoxic postconditioning as well as significant similarity between the adaptive pathways activated by various postconditioning methods, which are far from being fully understood.
10.1134/S000629791703018X
When the Brain Yearns for Oxygen.
Leu Tristan,Schützhold Vera,Fandrey Joachim,Ferenz Katja B
Neuro-Signals
Nearly 30 years ago hypoxia-inducible factor (HIF) was described as a protein complex bound to regulatory DNA sequences termed hypoxia response elements because HIF binding induced transcription of the erythropoietin gene under hypoxia. However, it soon became clear that HIF is part of a ubiquitous cellular oxygen sensing system, which ensures finely tuned control of HIF abundance and activity in dependence of the cellular oxygen tension. For their discoveries of how cells sense and adapt to oxygen availability Gregg L. Semenza, William G. Kaelin Jr. and Sir Peter J. Ratcliffe received the Nobel Prize in Physiology or Medicine 2019. The Nobel laureates' pioneering work on cellular oxygen sensing has unraveled that HIF has numerous target genes reflecting its multiple functions in cellular metabolism and adaptation to different levels of oxygen. Importantly, HIF is also crucial for the development of the nervous system. HIF has an influence on different neural cell types regarding neurogenesis, maturation and apoptosis. Furthermore, HIF is involved in pathophysiological processes of the brain like stroke and Alzheimer's disease resulting in the development of HIF-related therapeutic approaches.
10.33594/000000199
Roles of HIFs and VEGF in angiogenesis in the retina and brain.
Rattner Amir,Williams John,Nathans Jeremy
The Journal of clinical investigation
Vascular development in the mammalian retina is a paradigm for CNS vascular development in general, and its study is revealing fundamental mechanisms that explain the efficacy of antiangiogenic therapies in retinal vascular disease. During development of the mammalian retina, hypoxic astrocytes are hypothesized to secrete VEGF, which attracts growing endothelial cells as they migrate radially from the optic disc. However, published tests of this model using astrocyte-specific deletion of Vegf in the developing mouse retina appear to contradict this theory. Here, we report that selectively eliminating Vegf in neonatal retinal astrocytes with a Gfap-Cre line that recombines with approximately 100% efficiency had no effect on proliferation or radial migration of astrocytes, but completely blocked radial migration of endothelial cells, strongly supporting the hypoxic astrocyte model. Using additional Cre driver lines, we found evidence for essential and partially redundant actions of retina-derived (paracrine) and astrocyte-derived (autocrine) VEGF in controlling astrocyte proliferation and migration. We also extended previous studies by showing that HIF-1α in retinal neurons and HIF-2α in Müller glia play distinct roles in retinal vascular development and disease, adding to a growing body of data that point to the specialization of these 2 hypoxia-sensing transcription factors.
10.1172/JCI126655
Pericyte hypoxia-inducible factor-1 (HIF-1) drives blood-brain barrier disruption and impacts acute ischemic stroke outcome.
Angiogenesis
Pericytes play essential roles in blood-brain barrier integrity and their dysfunction is implicated in neurological disorders such as stroke although the underlying mechanisms remain unknown. Hypoxia-inducible factor-1 (HIF-1), a master regulator of injury responses, has divergent roles in different cells especially during stress scenarios. On one hand HIF-1 is neuroprotective but on the other it induces vascular permeability. Since pericytes are critical for barrier stability, we asked if pericyte HIF-1 signaling impacts barrier integrity and injury severity in a mouse model of ischemic stroke. We show that pericyte HIF-1 loss of function (LoF) diminishes ischemic damage and barrier permeability at 3 days reperfusion. HIF-1 deficiency preserved barrier integrity by reducing pericyte death thereby maintaining vessel coverage and junctional protein organization, and suppressing vascular remodeling. Importantly, considerable improvements in sensorimotor function were observed in HIF-1 LoF mice indicating that better vascular functionality post stroke improves outcome. Thus, boosting vascular integrity by inhibiting pericytic HIF-1 activation and/or increasing pericyte survival may be a lucrative option to accelerate recovery after severe brain injury.
10.1007/s10456-021-09796-4
Polysaccharide extracted from Potentilla anserina L ameliorate acute hypobaric hypoxia-induced brain impairment in rats.
Shi Jipeng,Wang Jinhui,Zhang Ji,Li Xiaolin,Tian Xiuyu,Wang Weigang,Wang Peng,Li Maoxing
Phytotherapy research : PTR
High altitude cerebral edema (HACE) is a high altitude malady caused by acute hypobaric hypoxia (AHH), in which pathogenesis is associated with oxidative stress and inflammatory cytokines. Potentilla anserina L is mainly distributed in Tibetan Plateau, and its polysaccharide possesses many physiological and pharmacological properties. In the present study, the protective effect and potential treatment mechanism of Potentilla anserina L polysaccharide (PAP) in HACE were explored. First, we measured the brain water content and observed the pathological changes in brain tissues, furthermore, malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and glutathione (GSH) were evaluated by kits. Finally, the protein contents and mRNA expressions of pro-inflammatory (IL-1β, IL-6, TNF-α, vascular endothelial cell growth factor [VEGF], NF-κB, and hypoxia inducible factor-1 α [HIF-1α]) were detected by ELISA kits, RT-PCR, and western blotting. The results demonstrated that PAP reduced the brain water content, alleviated brain tissue injury, reduce the levels of MDA and NO, and increased the activity of SOD and GSH level. In addition, PAP blocking the NF-κB and HIF-1α signaling pathway activation inhibited the generation of downstream pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, and VEGF). Therefore, PAP has a potential to treat and prevent of HACE by suppression of oxidative stress and inflammatory response.
10.1002/ptr.6691