Activation of hypoxia-inducible factors in hyperoxia through prolyl 4-hydroxylase blockade in cells and explants of primate lung

Asikainen, Tiina M.; Schneider, Barbara; Waleh, Nahid; Clyman, Ronald I.; Ho, Wen‐Bin; Flippin, Lee A.; Günzler, Volkmar; White, Carl W.

doi:10.1073/pnas.0504520102

Cited by 82 publications

(69 citation statements)

References 49 publications

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“…In the current study, we found that incubation of A549 cells in 95% O 2 fails to alter HIF-1α protein expression at 4 hours and beyond, but increases HIF-2α during recovery only. These outcomes are consistent with those recently reported by Asikainen and colleagues, demonstrating that exposure of A549 cells to 24 hours of hyperoxia does not influence VEGF mRNA, HIF-1α, HIF-2α protein, or total cell-associated VEGF protein levels [30]. Augmented HIF-2α protein expression in the absence of changes in VEGF mRNA expression during recovery may indicate that HIF-2α accumulation is exclusively cytoplasmic.…”

Section: Discussionsupporting

confidence: 82%

Hyperoxia enhances VEGF release from A549 cells via post-transcriptional processes

Shenberger

Zhang

Powell

et al. 2007

Free Radical Biology and Medicine

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Exposure of animals to hyperoxia decreases lung VEGF mRNA expression concomitant with an acute increase in VEGF protein within the epithelial lining fluid (ELF). The VEGF concentration in ELF is in excess of that found in the plasma, leading to the hypothesis that hyperoxia stimulates the release of VEGF protein from stores within the extracellular matrix. To test this hypothesis in a cell culture system, we exposed A549 cells to 95% O 2 for 48 hrs followed by recovery in room air

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Section: Discussionsupporting

confidence: 82%

Hyperoxia enhances VEGF release from A549 cells via post-transcriptional processes

Shenberger

Zhang

Powell

et al. 2007

Free Radical Biology and Medicine

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“…Thereby, DMOG resulted in significant reduction of apoptosis in the postischemic myocardium (Natarajan et al, 2009). Moreover, DMOG can exert cell-toxic properties, especially at higher doses (Asikainen et al, 2005). DMOG is a nonselective PHD inhibitor expected to interfere with all 2-OG-dependent oxygenases affecting a number of important cellular processes such as DNA repair, carnitine biosynthesis, and collagen modifications, and most likely many other functions within the cell, including the Krebs cycle, which were not accounted for (Loenarz and Schofield, 2008).…”

Section: Discussionmentioning

confidence: 99%

Neuroprotection by Dimethyloxalylglycine following Permanent and Transient Focal Cerebral Ischemia in Rats

Nagel

Papadakis

Chen

et al. 2010

J Cereb Blood Flow Metab

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Dimethyloxalylglycine (DMOG) is an inhibitor of prolyl-4-hydroxylase domain (PHD) enzymes that regulate the stability of hypoxia-inducible factor (HIF). We investigated the effect of DMOG on the outcome after permanent and transient middle cerebral artery occlusion (p/tMCAO) in the rat. Before and after pMCAO, rats were treated with 40 mg/kg, 200 mg/kg DMOG, or vehicle, and with 40 mg/kg or vehicle after tMCAO. Serial magnetic resonance imaging (MRI) was performed to assess infarct evolution and regional cerebral blood flow (rCBF). Both doses significantly reduced infarct volumes, but only 40 mg/kg improved the behavior after 24 hours of pMCAO. Animals receiving 40 mg/kg were more likely to maintain rCBF values above 30% from the contralateral hemisphere within 24 hours of pMCAO. DMOG after tMCAO significantly reduced the infarct volumes and improved behavior at 24 hours and 8 days and also improved the rCBF after 24 hours. A consistent and significant upregulation of both mRNA and protein levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) was associated with the observed neuroprotection, although this was not consistently related to HIF-1a levels at 24 hours and 8 days. Thus, DMOG afforded neuroprotection both at 24 hours after pMCAO and at 24 hours and 8 days after tMCAO. This effect was associated with an increase of VEGF and eNOS and was mediated by improved rCBF after DMOG treatment.

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“…The consequential increase in proangiogenic molecules like Epo and VEGF may be a result of systemic synthesis in the liver and kidney, in addition to local production from retinal cells. Critically, the use of small molecules like DMOG enhances the opportunity to regulate therapeutic angiogenesis in the absence of conventional gene therapy (23)(24)(25) or stem cell therapy (26). In fact, the overwhelming induction of Epo protein synthesis by DMOG and the reported effects of Epo on mobilization of erythroid precursor cells (27)(28)(29) suggest that targeting HIF activation by small-molecule inhibition of HIF-␣ subunit degradation could be a novel therapeutic approach for the treatment of ROP and other ischemia-induced proliferative retinopathies.…”

Section: Discussionmentioning

confidence: 99%

Prolyl hydroxylase inhibition during hyperoxia prevents oxygen-induced retinopathy

Sears

Hoppe²,

Ebrahem³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

102

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Oxygen-induced retinopathy (OIR) in the mouse, like the analogous human disease retinopathy of prematurity, is an ischemic retinopathy dependent on oxygen-induced vascular obliteration. We tested the hypothesis that chemically overriding the oxygeninduced downregulation of hypoxia-inducible factor (HIF) activity would prevent vascular obliteration and subsequent pathologic neovascularization in the OIR model. Because the degradation of HIF-1␣ is regulated by prolyl hydroxylases, we examined the effect of systemic administration of a prolyl hydroxylase inhibitor, dimethyloxalylglycine, in the OIR model. Our results determine that stabilizing HIF activity in the early phase of OIR prevents the oxygen-induced central vessel loss and subsequent vascular tortuosity and tufting that is characteristic of OIR. Overall, these findings imply that simulating hypoxia chemically by stabilizing HIF activity during the causative ischemia phase (hyperoxia) of retinopathy of prematurity may be of therapeutic value in preventing progression to the proliferative stage of the disease.dimethyloxalylglycine ͉ erythropoeitin ͉ hypoxia-inducible factor ͉ retinopathy of prematurity ͉ vascular endothelial growth factor R etinopathy of prematurity (ROP) is a retinovascular disease of severely premature infants characterized by neovascularization at the intersection of developed, vascularized retina and undeveloped avascular retina. ROP has two phases, based on the oxygen-regulated expression of VEGF (1, 2). Phase I begins at birth when the infant is placed into hyperoxia, which results in a reduction in the secretion of VEGF that is associated with oxygen-induced vascular obliteration. Phase II is a hypoxic state created by weaning of oxygen supplementation and increased retinal metabolic demand exacerbated by vessel loss from phase I. Phase II is characterized by an overexpression of growth factors, such as VEGF, from the ischemic retina, resulting in pathologic neovascularization. The central roles that hyperoxia and hypoxia play in the development of ROP suggest a critical need for studying the role of oxygen and oxygen-regulated transcription factors such as hypoxia-inducible factor (HIF), their relationship to ischemia, and the subsequent development of the disease. Although much attention has been focused on the treatment of the angiogenic phase by VEGF and HIF inhibitors (3-5), we hypothesized that preventing the oxygen-induced downregulation of HIF in the initial phase of ROP would result in a protective effect and loss of progression to the angiogenic phase II of the disease.HIF-1, and its related isoform HIF-2, are multimeric oxygenregulated transcription factors critical to vascular development and maintenance (6, 7). HIF-1 and -2 are homologous heterodimers composed of inducible ␣ and constitutive ␤ subunits (8, 9). The stability of HIF-1␣ is regulated by prolyl hydroxylases (PHD), which induce hydroxylation on two proline residues (Pro-402 and Pro-564) within the oxygen degradation domain (ODD) (10,11). This enables the inter...

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Activation of hypoxia-inducible factors in hyperoxia through prolyl 4-hydroxylase blockade in cells and explants of primate lung

Abstract: angiogenesis ͉ prematurity ͉ bronchopulmonary dysplasia ͉ alveolization

Cited by 82 publications

References 49 publications

Hyperoxia enhances VEGF release from A549 cells via post-transcriptional processes

Hyperoxia enhances VEGF release from A549 cells via post-transcriptional processes

Neuroprotection by Dimethyloxalylglycine following Permanent and Transient Focal Cerebral Ischemia in Rats

Prolyl hydroxylase inhibition during hyperoxia prevents oxygen-induced retinopathy

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