Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1−/− mice

Scortegagna, Marzia; Ding, Kan; Oktay, Yavuz; Gaur, Arti; Thurmond, Frederick A.; Lv, Yan; Marck, Brett T.; Matsumoto, Alvin M.; Shelton, John M.; Richardson, James A.; Bennett, Michael J.; Garcia, Joseph A.

doi:10.1038/ng1266

Cited by 453 publications

(451 citation statements)

References 49 publications

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“…Although HIF-2 expression levels remained constant, there appeared to be a significant, albeit conservative, increase in transcriptional activity under hypoxic conditions. With respect to functional activities of this HIF isoform, unlike the case in most other tissues, HIF-2 failed to increase the transcriptional activities of SOD2 and frataxin, 2 common target genes involved in radical dismutation (15,16). However, under hypoxic conditions, HIF-2 regulated the expression and promoter activity of cited2, which in turn modulated HIF-1-and HIF-2-mediated VEGF expression.…”

Section: Discussionmentioning

confidence: 85%

“…Recent evidence suggests that HIF-1 and HIF-2 are not redundant, and that the relative importance of each of the homologs, in response to hypoxia, varies among different cell types (14). For example, unlike HIF-1, HIF-2 regulates expression of a number of unique genes including superoxide dismutase 2 (SOD2), catalase, frataxin, Wisp2, Oct4, and cited2 (15)(16)(17)(18). Recently, it was documented that HIF-2 regulates matrix gene expression in articular chondrocytes (19,20).…”

mentioning

confidence: 99%

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Cited2 modulates hypoxia‐inducible factor–dependent expression of vascular endothelial growth factor in nucleus pulposus cells of the rat intervertebral disc

Agrawal¹,

Gajghate²,

Smith³

et al. 2008

Arthritis & Rheumatism

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Objective. To determine whether nucleus pulposus cells of the intervertebral disc express hypoxiainducible factor 2␣ (HIF-2␣), and to assess the role of HIF-1 and HIF-2 in controlling cited2 and vascular endothelial growth factor (VEGF) expression.Methods. Rat cells were cultured under normoxic (21% O 2 ) or hypoxic (2% O 2 ) conditions, and expression and promoter activity of HIF-2 target genes were evaluated. Gain-or loss-of-function experiments were performed to investigate the contribution of HIF isoforms to cited2 activity as well as the role of cited2 in regulating VEGF expression.Results. We found that HIF-2␣ protein was expressed in vivo and that protein and messenger RNA expression were similar under both normoxic and hypoxic conditions. However, there was a significant increase in HIF-2␣ transactivation under hypoxic conditions. With respect to functional activity, unlike the case in most other tissues, HIF-2 failed to increase the transcriptional activities of superoxide dismutase 2 and frataxin, 2 common target genes involved in radical dismutation. However, under hypoxic conditions, HIF-2 preferentially regulated the expression and promoter activity of cited2, a p300 binding protein. When HIF-2␣ or HIF-1␣ was suppressed, cited2 promoter activity was inhibited. Finally, we showed that forced expression or suppression of cited2 resulted in corresponding changes in expression of VEGF, a common target gene for HIF-1 and HIF-2 in the nucleus pulposus cells.Conclusion. Results of this study indicate that in nucleus pulposus cells, HIF-2 and HIF-1 modulate their own transcriptional activity through cited2. We suggest that the 2 arms of the regulatory circuit serve to maintain survival activities and inhibit angiogenesis in the healthy disc.

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Section: Discussionmentioning

confidence: 85%

mentioning

confidence: 99%

Cited2 modulates hypoxia‐inducible factor–dependent expression of vascular endothelial growth factor in nucleus pulposus cells of the rat intervertebral disc

Agrawal¹,

Gajghate²,

Smith³

et al. 2008

Arthritis & Rheumatism

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“…Global Hif2a deletion also induces embryonic or perinatal lethality, which is associated with bradycardia (16), mitochondrial dysfunction (17), and defective lung and vascular development (18). However, mice developed normally after endothelial deletion of Hif2a but displayed aberrant endothelial cell (EC) ultrastructure, coupled with decreased expression of extracellular matrix proteins and increased microvessel leakiness (19).…”

Section: Introductionmentioning

confidence: 99%

HIF2α signaling inhibits adherens junctional disruption in acute lung injury

Gong¹,

Rehman²,

Tang³

et al. 2015

J. Clin. Invest.

119

132

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“…In addition, unlike the present study, the study by Pfander et al did not investigate HIF-2␣. However, mouse articular chondrocytes have been shown to express HIF-2␣ protein (19); moreover, HIF-2␣ Ϫ/Ϫ mice (which die within days after birth) are very small in size, suggesting abnormal endochondral bone growth (20). Based on our findings of the importance of HIF-2␣ in human articular chondrocytes, a cartilage-specific and inducible HIF-2␣ knockout is being developed to investigate its contribution to maintenance of articular cartilage in an in vivo setting.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia‐inducible factor 2α is essential for hypoxic induction of the human articular chondrocyte phenotype

Lafont¹,

Talma²,

Murphy³

2007

Arthritis & Rheumatism

134

155

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Objective. To uncover the mechanism by which hypoxia enhances cartilage matrix synthesis by human articular chondrocytes.Methods. The hypoxic response was investigated by exposing normal (nonarthritic) human articular chondrocyte cultures to 20% oxygen and 1% oxygen. Induction of the differentiated phenotype was confirmed at the gene and protein levels. In its first reported application in human articular chondrocytes, the RNA interference method was used to directly investigate the role of specific transcription factors in this process. Small interfering RNA directed against hypoxiainducible factor 1␣ (HIF-1␣), HIF-2␣, and SOX9 were delivered by lipid-based transfection of primary and passaged human articular chondrocytes. The effect of each knockdown on hypoxic induction of the chondrocyte phenotype was assessed.Results. Hypoxia enhanced matrix synthesis and SOX9 expression of human articular chondrocytes at both the gene and protein levels. Although HIF-1␣ knockdown had no effect, depletion of HIF-2␣ abolished this hypoxic induction. Thus, we provide the first evidence that HIF-2␣, but not HIF-1␣, is essential for hypoxic induction of the human articular chondrocyte phenotype. In addition, depletion of SOX9 prevented hypoxic induction of matrix genes, indicating that the latter are not direct HIF targets but are up-regulated by hypoxia via SOX9.Conclusion. Based on our data, we propose a novel mechanism whereby hypoxia promotes cartilage matrix synthesis specifically through HIF-2␣-mediated SOX9 induction of key cartilage genes. These findings have potential application for the development of cartilage repair therapies.Being avascular, cartilage has a low oxygen concentration (1,2). Chondrocytes, the unique resident cells, are therefore adapted to these hypoxic conditions, e.g., by having lower levels of oxidative phosphorylation (3) and enhanced anaerobic glycolysis (4). Furthermore, recent studies suggest that hypoxia triggers essential positive signals for the chondrocyte phenotype beyond such survival responses. Indeed, we previously reported that reduced oxygen tension increases levels of the cartilage matrix genes COL2A1 and aggrecan and the cartilage transcription factor SOX9 in cultured articular chondrocytes (5,6). Domm and colleagues also showed a positive effect of hypoxia on Col␣1(II) levels in bovine chondrocytes (7). Hypoxia has been shown to promote chondrogenic differentiation of mesenchymal stem cells, and it was recently shown that the mouse Sox9 promoter is activated by hypoxia in mouse mesenchymal cells (8).In various cell types, hypoxic effects have been shown to be mediated by hypoxia-inducible factor (HIF) transcription factors. These proteins belong to the Per-ARNT-Sim (PAS) subfamily of basic helix-loop-helix (bHLH) transcription factors and consist of an ␣ subunit and a ␤ subunit (9). Under conditions of normoxia, HIF-1␣ is hydroxylated on specific proline residues, ubiquitinated through interaction with the von HippelLindau tumor suppressor protein, pVHL, and subsequently degraded b...

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Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1−/− mice

Cited by 453 publications

References 49 publications

Cited2 modulates hypoxia‐inducible factor–dependent expression of vascular endothelial growth factor in nucleus pulposus cells of the rat intervertebral disc

Cited2 modulates hypoxia‐inducible factor–dependent expression of vascular endothelial growth factor in nucleus pulposus cells of the rat intervertebral disc

HIF2α signaling inhibits adherens junctional disruption in acute lung injury

Hypoxia‐inducible factor 2α is essential for hypoxic induction of the human articular chondrocyte phenotype

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