Association of EGLN1 gene with high aerobic capacity of Peruvian Quechua at high altitude

Highland native Andeans have resided at altitude for millennia. They display high aerobic capacity (VO2max) at altitude, which may be a reflection of genetic adaptation to hypoxia. Previous genomewide (GW) scans for natural selection have nominated Egl-9 homolog 1 gene (EGLN1) as a candidate gene. The encoded protein, EGLN1/PHD2, is an O2 sensor that controls levels of the Hypoxia Inducible Factor-α (HIF-α), which regulates the cellular response to hypoxia. From GW association and analysis of covariance performed on a total sample of 429 Peruvian Quechua and 94 US lowland referents, we identified 5 EGLN1 SNPs associated with higher VO2max (L⋅min−1 and mL⋅min−1⋅kg−1) in hypoxia (rs1769793, rs2064766, rs2437150, rs2491403, rs479200). For 4 of these SNPs, Quechua had the highest frequency of the advantageous (high VO2max) allele compared with 25 diverse lowland comparison populations from the 1000 Genomes Project. Genotype effects were substantial, with high versus low VO2max genotype categories differing by ∼11% (e.g., for rs1769793 SNP genotype TT = 34.2 mL⋅min−1⋅kg−1 vs. CC = 30.5 mL⋅min−1⋅kg−1). To guard against spurious association, we controlled for population stratification. Findings were replicated for EGLN1 SNP rs1769793 in an independent Andean sample collected in 2002. These findings contextualize previous reports of natural selection at EGLN1 in Andeans, and support the hypothesis that natural selection has increased the frequency of an EGLN1 causal variant that enhances O2 delivery or use during exercise at altitude in Peruvian Quechua.

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Regulation of the Hypoxia-Inducible Factor (HIF) by Pro-Inflammatory Cytokines

Cells ◽

10.3390/cells10092340 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2340

Author(s):

Mykyta I. Malkov ◽

Chee Teik Lee ◽

Cormac T. Taylor

Keyword(s):

Inflammatory Cytokines ◽

Cellular Response ◽

Inflammatory Diseases ◽

Hypoxia Inducible Factor ◽

Wide Range ◽

Inflammatory Stimuli ◽

Factor Α ◽

Hif Pathway ◽

The Impact ◽

Pro Inflammatory Cytokines

Hypoxia and inflammation are frequently co-incidental features of the tissue microenvironment in a wide range of inflammatory diseases. While the impact of hypoxia on inflammatory pathways in immune cells has been well characterized, less is known about how inflammatory stimuli such as cytokines impact upon the canonical hypoxia-inducible factor (HIF) pathway, the master regulator of the cellular response to hypoxia. In this review, we discuss what is known about the impact of two major pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), on the regulation of HIF-dependent signaling at sites of inflammation. We report extensive evidence for these cytokines directly impacting upon HIF signaling through the regulation of HIF at transcriptional and post-translational levels. We conclude that multi-level crosstalk between inflammatory and hypoxic signaling pathways plays an important role in shaping the nature and degree of inflammation occurring at hypoxic sites.

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Tumor Necrosis Factor-α Causes Accumulation of a Ubiquitinated Form of Hypoxia Inducible Factor-1α through a Nuclear Factor-κB-Dependent Pathway

Molecular Biology of the Cell ◽

10.1091/mbc.e02-09-0598 ◽

2003 ◽

Vol 14 (6) ◽

pp. 2216-2225 ◽

Cited By ~ 109

Author(s):

Jie Zhou ◽

Tobias Schmid ◽

Bernhard Brüne

Keyword(s):

Hypoxia Inducible Factor ◽

Nuclear Factor Κb ◽

Metabolic Adaptation ◽

Adaptation To Hypoxia ◽

Nuclear Factor ◽

Human Embryonic Kidney Cells ◽

Von Hippel Lindau ◽

Hypoxia Inducible Factor 1 ◽

Tnf Α ◽

Factor Α

Hypoxia-inducible factor-1 (HIF-1) is a regulator of metabolic adaptation to hypoxia. It is now appreciated that HIF-1α accumulation is achieved under normoxic conditions by various factors, such as TNF-α. Here, it was our intention to gain insight into the signaling mechanisms used by TNF-α to stimulate HIF-1α. In tubular LLC-PK1or human embryonic kidney cells, TNF-α induced accumulation of HIF-1α protein but not HIF-1α mRNA. Blocking nuclear factor (NF)-κB with sulfasalazine or expression of an IκB superrepressor attenuated HIF-1α accumulation, whereas transfection of active p50/p65-NF-κB subunits mimicked a TNF-α response. Experiments with actinomycin D and cycloheximide also pointed to a transcriptional and translational process in facilitating the TNF-α response. Interestingly, and in contrast to established hypoxic signaling concepts, TNF-α elicited HIF-1α accumulation in a ubiquitinated form that still bound the von Hippel-Lindau (pVHL) protein. These data indicate that HIF-1α accumulation by TNF-α demands the NF-κB pathway, preserves ubiquitination of HIF-1α, and allows the HIF-1α-pVHL interaction.

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Skeletal muscle mass and the reduction ofV˙o 2 max in trained older subjects

Journal of Applied Physiology ◽

10.1152/jappl.1997.82.5.1411 ◽

1997 ◽

Vol 82 (5) ◽

pp. 1411-1415 ◽

Cited By ~ 129

Author(s):

David N. Proctor ◽

Michael J. Joyner

Keyword(s):

Skeletal Muscle ◽

Older Women ◽

Muscle Mass ◽

Aerobic Capacity ◽

Skeletal Muscle Mass ◽

Muscle Blood Flow ◽

Older Men ◽

Analysis Of Covariance ◽

Active Muscle ◽

Older Subjects

Proctor, David N., and Michael J. Joyner. Skeletal muscle mass and the reduction ofV˙o 2 max in trained older subjects. J. Appl. Physiol.82(5): 1411–1415, 1997.—The role of skeletal muscle mass in the age-associated decline in maximal O2 uptake (V˙o 2 max) is poorly defined because of confounding changes in muscle oxidative capacity and in body fat and the difficulty of quantifying active muscle mass during exercise. We attempted to clarify these issues by examining the relationship between several indexes of muscle mass, as estimated by using dual-energy X-ray absorptiometry and treadmillV˙o 2 max in 32 chronically endurance-trained subjects from four groups ( n = 8/group): young men (20–30 yr), older men (56–72 yr), young women (19–31 yr), and older women (51–72 yr).V˙o 2 max per kilogram body mass was 26 and 22% lower in the older men (45.9 vs. 62.0 ml ⋅ kg−1 ⋅ min−1) and older women (40.0 vs. 51.5 ml ⋅ kg−1 ⋅ min−1). These age differences were reduced to 14 and 13%, respectively, whenV˙o 2 max was expressed per kilogram of appendicular muscle. When appropriately adjusted for age and gender differences in appendicular muscle mass by analysis of covariance, whole bodyV˙o 2 max was 0.50 ± 0.09 l/min less ( P < 0.001) in the older subjects. This effect was similar in both genders. These findings suggest that the reducedV˙o 2 max seen in highly trained older men and women relative to their younger counterparts is due, in part, to a reduced aerobic capacity per kilogram of active muscle independent of age-associated changes in body composition, i.e., replacement of muscle tissue by fat. Because skeletal muscle adaptations to endurance training can be well maintained in older subjects, the reduced aerobic capacity per kilogram of muscle likely results from age-associated reductions in maximal O2 delivery (cardiac output and/or muscle blood flow).

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Variations within oxygen-regulated gene expression in humans

Journal of Applied Physiology ◽

10.1152/japplphysiol.90578.2008 ◽

2009 ◽

Vol 106 (1) ◽

pp. 212-220 ◽

Cited By ~ 19

Author(s):

Jerome T. S. Brooks ◽

Gareth P. Elvidge ◽

Louisa Glenny ◽

Jonathan M. Gleadle ◽

Chun Liu ◽

...

Keyword(s):

Cellular Response ◽

Genetic Manipulation ◽

Hypoxia Inducible Factor ◽

Hereditary Disease ◽

Peripheral Blood Lymphocytes ◽

Cellular Level ◽

Normal Individuals ◽

Regulated Gene Expression ◽

Open Question ◽

Hif Pathway

The effects of hypoxia on gene transcription are mainly mediated by a transcription factor complex termed hypoxia-inducible factor (HIF). Genetic manipulation of animals and studies of humans with rare hereditary disease have shown that modifying the HIF pathway affects systems-level physiological responses to hypoxia. It is, however, an open question whether variations in systems-level responses to hypoxia between individuals could arise from variations within the HIF system. This study sought to determine whether variations in the responsiveness of the HIF system at the cellular level could be detected between normal individuals. Peripheral blood lymphocytes (PBL) were isolated on three separate occasions from each of 10 healthy volunteers. After exposure of PBL to eight different oxygen tensions ranging from 20% to 0.1%, the expression levels of four HIF-regulated transcripts involved in different biological pathways were measured. The profile of expression of all four transcripts in PBL was related to oxygen tension in a curvilinear manner. Double logarithmic transformation of these data resulted in a linear relationship that allowed the response to be parameterized through a gradient and intercept. Analysis of variance (ANOVA) on these parameters showed that the level of between-subject variation in the gradients of the responses that was common across all four HIF-regulated transcripts was significant ( P = 0.008). We conclude that statistically significant variation within the cellular response to hypoxia can be detected between normal humans. The common nature of the variability across all four HIF-regulated genes suggests that the source of this variation resides within the HIF system itself.

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Hypoxia-inducible factor–1 and associated upstream and downstream proteins in the pathophysiology and management of glioblastoma

Neurosurgical FOCUS ◽

10.3171/2014.9.focus14496 ◽

2014 ◽

Vol 37 (6) ◽

pp. E8 ◽

Cited By ~ 18

Author(s):

Matthew Womeldorff ◽

David Gillespie ◽

Randy L. Jensen

Keyword(s):

Cellular Response ◽

Treatment Options ◽

Hypoxia Inducible Factor ◽

Hypoxia Inducible Factor 1 ◽

Poor Patient ◽

Growth Development ◽

The Relationship ◽

Insight Into ◽

Upstream Regulators

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with an exceptionally poor patient outcome despite aggressive therapy including surgery, radiation, and chemotherapy. This aggressive phenotype may be associated with intratumoral hypoxia, which probably plays a key role in GBM tumor growth, development, and angiogenesis. A key regulator of cellular response to hypoxia is the protein hypoxia-inducible factor–1 (HIF-1). An examination of upstream hypoxic and nonhypoxic regulation of HIF-1 as well as a review of the downstream HIF-1–regulated proteins may provide further insight into the role of this transcription factor in GBM pathophysiology. Recent insights into upstream regulators that intimately interact with HIF-1 could provide potential therapeutic targets for treatment of this tumor. The same is potentially true for HIF-1–mediated pathways of glycolysis-, angiogenesis-, and invasion-promoting proteins. Thus, an understanding of the relationship between HIF-1, its upstream protein regulators, and its downstream transcribed genes in GBM pathogenesis could provide future treatment options for the care of patients with these tumors.

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Oxygen sensing and molecular adaptation to hypoxia

Physiological Reviews ◽

10.1152/physrev.1996.76.3.839 ◽

1996 ◽

Vol 76 (3) ◽

pp. 839-885 ◽

Cited By ~ 815

Author(s):

H. F. Bunn ◽

R. O. Poyton

Keyword(s):

Transcription Factors ◽

Mammalian Cells ◽

Critical Role ◽

Hypoxia Inducible Factor ◽

Signal Transduction Pathway ◽

Adaptation To Hypoxia ◽

Adaptive Responses ◽

Expression Of Genes ◽

Activation Of Transcription ◽

Activation Of Oxygen

This review focuses on the molecular stratagems utilized by bacteria, yeast, and mammals in their adaptation to hypoxia. Among this broad range of organisms, changes in oxygen tension appear to be sensed by heme proteins, with subsequent transfer of electrons along a signal transduction pathway which may depend on reactive oxygen species. These heme-based sensors are generally two-domain proteins. Some are hemokinases, while others are flavohemoproteins [flavohemoglobins and NAD(P)H oxidases]. Hypoxia-dependent kinase activation of transcription factors in nitrogen-fixing bacteria bears a striking analogy to the phosphorylation of hypoxia inducible factor-1 (HIF-1) in mammalian cells. Moreover, redox chemistry appears to play a critical role both in the trans-activation of oxygen-responsive genes in unicellular organisms as well as in the activation of HIF-1. In yeast and bacteria, regulatory operons coordinate expression of genes responsible for adaptive responses to hypoxia and hyperoxia. Similarly, in mammals, combinatorial interactions of HIF-1 with other identified transcription factors are required for the hypoxic induction of physiologically important genes.

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Anterior Diffuse Retinoblastoma: Mutational Analysis and Immunofluorescence Staining

Archives of Pathology & Laboratory Medicine ◽

10.5858/133.8.1215 ◽

2009 ◽

Vol 133 (8) ◽

pp. 1215-1218

Author(s):

Michelle B. Crosby ◽

G. Baker Hubbard ◽

Brenda L. Gallie ◽

Hans E. Grossniklaus

Keyword(s):

Growth Factor ◽

Transforming Growth Factor ◽

Mutational Analysis ◽

Hypoxia Inducible Factor ◽

Transforming Growth Factor Β ◽

Immunofluorescence Staining ◽

Vascular Endothelial ◽

Factor Α ◽

Oxide Synthase ◽

Endothelial Growth Factor

Abstract Retinoblastoma is the most common primary intraocular tumor of childhood and may be heritable or occur sporadically. Anterior diffuse retinoblastoma is an uncommon variant that is thought to be sporadic. We describe a child with anterior diffuse retinoblastoma who presented with a pseudohypopyon. Genetic analysis showed a germline mutation of the RB1 allele that is potentially heritable. Immunofluorescence staining was positive for transforming growth factor β and for vascular endothelial growth factor and negative for inducible nitric oxide synthase and for hypoxia inducible factor α in the tumor seeds, indicating acquisition of nonischemia-mediated survival factors of the tumor seeds in the aqueous humor.

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Abstract 396: Inhibition of Prolyl Hydroxylase Domain-containing Protein Downregulates Vascular Angiotensin II Type 1 Receptor

Hypertension ◽

10.1161/hyp.60.suppl_1.a396 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Toshihiro Ichiki

Keyword(s):

Cellular Response ◽

Target Genes ◽

Interstitial Fibrosis ◽

Critical Role ◽

Hypoxia Inducible Factor ◽

Renin Angiotensin System ◽

Prolyl Hydroxylase ◽

Ang Ii ◽

Prolyl Hydroxylase Domain

Background: Prolyl hydroxylase domain-containing protein (PHD) mediates hydroxylation of hypoxia-inducible factor (HIF)-1α and thereby induces proteasomal degradation of HIF-1α. Inhibition of PHD by hypoxia or hypoxia mimetics such as cobalt chloride (CoCl2) stabilizes HIF-1 and increases the expression of target genes such as vascular endothelial growth factor (VEGF). Although hypoxia activates the systemic renin angiotensin system (RAS), the role of PHD in regulating RAS remains unknown. We examined the effect of PHD inhibition on the expression of angiotensin (Ang) II type 1 receptor (AT1R) and its signaling. Methods and Results: Hypoxia (1% O2), CoCl2 (100-300 μmol/L), and dimethyloxalylglycine (0.25-1.0 mmol/L), all known to inhibit PHD, reduced AT1R expression by 37.7±7.6, 39.6±8.4-69.7±9.9, and 13.4±6.1-25.2±7.0%, respectively (p<0.01) in cultured vascular smooth muscle cell. The same stimuli increased the expression of nuclear HIF-1α and VEGF (p<0.05), suggesting that PHD activity is inhibited. Knockdown of PHD2, a major isoform of PHDs, by RNA interference also reduced AT1R expression by 55.3±6.0% (p<0.01). CoCl2 decreased AT1R mRNA through transcriptional and posttranscriptional mechanisms (p<0.01 and <0.05, respectively). CoCl2 and PHD2 knockdown diminished Ang II-induced ERK phosphorylation (P<0.01). Over-expression of the constitutively active HIF-1α did not impact the AT1R gene promoter activity. Oral administration of CoCl2 (14 mg/kg/day) to C57BL/6J mice receiving Ang II infusion (490 ng/kg/min) for 4 weeks significantly reduced the expression of AT1R in the aorta by 60.9±11.3% (p<0.05) and attenuated coronary perivascular fibrosis by 85% (p<0.01) without affecting blood pressure. However, CoCl2 did not affect Ang II-induced renal interstitial fibrosis. Conclusion: PHD inhibition downregulates AT1R expression independently of HIF-1α, reduces the cellular response to Ang II, and attenuates profibrotic effect of Ang II on the coronary arteries. PHD inhibition may be beneficial for the treatment of cardiovascular diseases, in which activation of RAS plays a critical role.

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mTOR inhibition as a possible pharmacological target in the management of systemic inflammatory response and associated neuroinflammation by lipopolysaccharide challenge in rats

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2020-0487 ◽

2021 ◽

Author(s):

Demet Sinem Guden ◽

Meryem Temiz-Resitoglu ◽

Sefika Pınar Senol ◽

Deniz Kibar ◽

Sakir Necat Yilmaz ◽

...

Keyword(s):

Inflammatory Response ◽

Microglial Activation ◽

Critical Role ◽

Mammalian Target Of Rapamycin ◽

Hypoxia Inducible Factor ◽

B Cell Lymphoma ◽

Nuclear Factor Κb ◽

Systemic Inflammatory Response ◽

Mtor Inhibition ◽

Factor Α

Neuroinflammation plays a critical role during sepsis triggered by microglial activation. Mammalian target of rapamycin (mTOR) has gained attraction in neuroinflammation, however, the mechanism remains unclear. Our goal was to assess the effects of mTOR inhibition by rapamycin on inflammation, microglial activation, oxidative stress, and apoptosis associated with the changes in the inhibitor-κB (IκB)-α/nuclear factor-κB (NF-κB)/hypoxia-inducible factor-1α (HIF-1α) pathway activity following a systemic challenge with lipopolysaccharide (LPS). Rats received saline (10 ml/kg), LPS (10 mg/kg), and/or rapamycin (1 mg/kg) via intraperitoneally. Inhibition of mTOR by rapamycin blocked phosphorylated form of ribosomal protein S6, NF-κB p65 activity by increasing degradation of IκB-α in parallel with HIF-1α expression increased by LPS in the kidney, heart, lung, and brain tissues. Rapamycin attenuated the increment in the expression of tumor necrosis factor-α and interleukin-1β, the inducible nitric oxide synthase, gp91<sup>phox</sup>, and p47<sup>phox</sup> in addition to nitrite levels elicited by LPS in tissues or sera. Concomitantly, rapamycin treatment reduced microglial activation, brain expression of caspase-3, and Bcl-2-associated X protein while increased expression of B-cell lymphoma 2 induced by LPS. Overall, this study supports the hypothesis that mTOR contributes to the detrimental effect of LPS-induced systemic inflammatory response associated with neuroinflammation via IκB-α/NF-κB/HIF-1α signaling pathway.

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