HIF1A Reduces Acute Lung Injury by Optimizing Carbohydrate Metabolism in the Alveolar Epithelium

Eckle, Tobias; Brodsky, Kelley S.; Bonney, Megan; Packard, Thomas; Han, Jun; Borchers, Christoph H.; Mariani, Thomas J.; Kominsky, Douglas J.; Mittelbronn, Michel; Eltzschig, Holger K.

doi:10.1371/journal.pbio.1001665

Cited by 145 publications

(211 citation statements)

References 102 publications

(133 reference statements)

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“…30 More recently, HIF-1α-driven optimization of carbohydrate metabolism, also acquired with a nonspecific 2-oxoglutarate inhibitor analogue DMOG, during an inflammatory acute lung injury, provided lung protection and dampened inflammation. 31 The data available suggest that HIFα stabilization via HIF-P4H inhibition can modulate immunologic responses, making them potential therapeutic targets in the treatment of chronic inflammatory diseases. Our data provide evidence for the pharmacological use of HIF-P4H-2 inhibition for the prevention of atherosclerosis development, such therapy combining reductions in serum cholesterol levels with modulation of innate immunity and protection against inflammation.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Inducible Factor Prolyl 4-Hydroxylase-2 Inhibition Protects Against Development of Atherosclerosis

Rahtu‐Korpela

Määttä

Dimova

et al. 2016

ATVB

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Objective— Small-molecule hypoxia-inducible factor prolyl 4-hydroxylase (HIF-P4H) inhibitors are being explored in clinical studies for the treatment of anemia. HIF-P4H-2 (also known as PHD2 or EglN1) inhibition improves glucose and lipid metabolism and protects against obesity and metabolic dysfunction. We studied here whether HIF-P4H-2 inhibition could also protect against atherosclerosis. Approach and Results— Atherosclerosis development was studied in low-density lipoprotein (LDL) receptor–deficient mice treated with an oral HIF-P4H inhibitor, FG-4497, and in HIF-P4H-2-hypomorphic/C699Y-LDL receptor–mutant mice, all mice being fed a high-fat diet. FG-4497 administration to LDL receptor–deficient mice reduced the area of atherosclerotic plaques by ≈50% when compared with vehicle-treated controls and also reduced their weight gain, insulin resistance, liver and white adipose tissue (WAT) weights, adipocyte size, number of inflammation-associated WAT macrophage aggregates and the high-fat diet–induced increases in serum cholesterol levels. The levels of atherosclerosis-protecting circulating autoantibodies against copper-oxidized LDL were increased. The decrease in atherosclerotic plaque areas correlated with the reductions in weight, serum cholesterol levels, and WAT macrophage aggregates and the autoantibody increase. FG-4497 treatment stabilized HIF-1α and HIF-2α and altered the expression of glucose and lipid metabolism and inflammation-associated genes in liver and WAT. The HIF-P4H-2-hypomorphic/C699Y-LDL receptor–mutant mice likewise had a ≈50% reduction in atherosclerotic plaque areas, reduced WAT macrophage aggregate numbers, and increased autoantibodies against oxidized LDL, but did not have reduced serum cholesterol levels. Conclusions— HIF-P4H-2 inhibition may be a novel strategy for protecting against the development of atherosclerosis. The mechanisms involve beneficial modulation of the serum lipid profile and innate immune system and reduced inflammation.

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Section: Discussionmentioning

confidence: 99%

Hypoxia-Inducible Factor Prolyl 4-Hydroxylase-2 Inhibition Protects Against Development of Atherosclerosis

Rahtu‐Korpela

Määttä

Dimova

et al. 2016

ATVB

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“…DMOG (BML-EI347-0050, Enzo Life Science, Farmingdale, New York; 40 mg/kg in 100 µl saline) was i.v. injected 4h before every ITPP injection (18). FOLFOX (6 mg/kg oxaliplatin, followed 2h later by 90 mg/kg folinic acid and 50 mg/kg 5-fluorouracil, Sigma-Aldrich, Dorset, UK) was given 5x every other day either alone for monotherpay (akin to ITPP, Fig.…”

Section: Animal Procedures Treatment and Mri Imagingmentioning

confidence: 99%

Antihypoxic Potentiation of Standard Therapy for Experimental Colorectal Liver Metastasis through Myo-Inositol Trispyrophosphate

Limani¹,

Linecker²,

Kachaylo³

et al. 2016

Clinical Cancer Research

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PURPOSE: Tumor hypoxia activates hypoxia-inducible factors (Hifs), which induce a range of malignant changes including vascular abnormalities. Here, we determine whether inhibition of the hypoxic tumor response through myo-inositol trispyrophosphate (ITPP), a compound with antihypoxic properties, is able to cause prolonged vascular normalization that can be exploited to improve standardof-care treatment. EXPERIMENTAL DESIGN: We tested ITPP on two syngeneic orthotopic mouse models of lethal colorectal cancer liver metastasis. Tumors were monitored by MRI and analyzed for the hypoxic response and their malignant potential. A Hif activator and in vitro assays were used to define the working mode of ITPP. Hypoxic response and vasculature were re-evaluated 4 weeks after treatment. Finally, we determined survival following ITPP monotherapy, FOLFOX monotherapy, FOLFOX plus Vegf antibody, and FOLFOX plus ITPP, both overlapping and sequential. RESULTS: ITPP reduced tumor load, efficiently inhibited the hypoxic response, and improved survival. These effects were lost when mice were pretreated with a Hif activator. Its immediate effects on the hypoxic response, including an apparent normalization of tumor vasculature, persisted for at least 4 weeks after treatment cessation. Compared with FOLFOX alone, Vegf antibody combined with FOLFOX prolonged survival by <30%, whereas ITPP combined with FOLFOX extended survival by >140%, regardless of whether FOLFOX was given in overlap or after ITPP exposure. CONCLUSIONS: Our findings reveal a truly antihypoxic mechanism for ITPP and demonstrate the capacity of this nontoxic compound to potentiate the efficacy of existing anticancer treatment in a way amenable to clinical translation. Clin Cancer Res; 22(23); 5887-97. DOI: https://doi.org/10.1158/1078-0432. Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-125980 Accepted Version Originally published at: Limani, P; Linecker, M; Kachaylo, E; Tschuor, C; Kron, P; Schlegel, A; Ungethuem, U; Jang, J H; Georgiopoulou, S; Claude Nicolau, C; Lehn, J-M; Graf, R; Humar, B; Clavien, P-A (2016). Antihypoxic potentiation of standard therapy for experimental colorectal liver metastasis through myo-inositol trispyrophosphate. Clinical Cancer Research, 22 (23) Results. ITPP reduced tumor load, efficiently inhibited the hypoxic response, and improved survival. These effects were lost when mice were pretreated with a Hif activator. Its immediate effects on the hypoxic response, including an apparent normalization of tumor vasculature, persisted for at least four weeks after treatment cessation. Compared to FOLFOX alone, Vegf antibody combined with FOLFOX prolonged survival by <30%, whereas ITPP combined with FOLFOX extended survival by >140%, regardless of whether FOLFOX was given in overlap or after ITPP exposure. Conclusions.Our findings reveal a truly antihypoxic mechanism for ITPP and demonstrate the capacity of this nontoxic compound to potentiate the efficacy of existing antic...

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“…These observations suggest alterations of the hypoxic-adenosinergic axis in the pathogenesis of PH secondary to IPF. Stabilization of HIF-1A has also been shown to occur in the absence of hypoxic environments (17) through metabolic imbalances that have been observed in patients with PH (18). Taken together, these observations prompted us to evaluate whether alterations of the hypoxic-adenosine axis and metabolic imbalances leading to enhanced HIF-1A stabilization were apparent in patients with PH secondary to IPF.…”

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confidence: 99%

Altered Hypoxic–Adenosine Axis and Metabolism in Group III Pulmonary Hypertension

Garcia-Morales¹,

Chen²,

Weng³

et al. 2016

Am J Respir Cell Mol Biol

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Group III pulmonary hypertension (PH) is a highly prevalent and deadly lung disorder with limited treatment options other than transplantation. Group III PH affects patients with ongoing chronic lung injury, such as idiopathic pulmonary fibrosis (IPF). Between 30 and 40% of patients with IPF are diagnosed with PH. The diagnosis of PH has devastating consequences to these patients, leading to increased morbidity and mortality, yet the molecular mechanisms involved in the development of PH in patients with chronic lung disease remain elusive. Our hypothesis was that the hypoxic-adenosinergic system is enhanced in patients with group III PH compared with patients with IPF with no PH. Explanted lung tissue was analyzed for markers of the hypoxic-adenosine axis, including expression levels of hypoxiainducible factor (HIF)-1A, adenosine A2B receptor, CD73, and equilibrative nucleotide transporter-1. In addition, we assessed whether altered mitochondrial metabolism was present in these samples. Increased expression of HIF-1A was observed in tissues from patients with group III PH. These changes were consistent with increased evidence of adenosine accumulation in group III PH. A novel observation of our study was of evidence suggesting altered mitochondrial metabolism in lung tissue from group III PH leading to increased succinate levels that are able to further stabilize HIF-1A. Our data demonstrate that the hypoxic-adenosine axis is up-regulated in group III PH and that subsequent succinate accumulation may play a part in the development of group III PH.Keywords: group III pulmonary hypertension; adenosine A2B receptor; idiopathic pulmonary fibrosis; succinate; hypoxiainducible factor-1A Clinical RelevanceThis study shows that alterations in metabolism lead to enhanced activation of the hypoxic-adenosine axis that contribute to the development of pulmonary hypertension associated with idiopathic pulmonary fibrosis. These findings suggest that targeting elements of the hypoxic-adenosine axis could be used therapeutically for group III pulmonary hypertension, for which currently no effective strategies exist.

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HIF1A Reduces Acute Lung Injury by Optimizing Carbohydrate Metabolism in the Alveolar Epithelium

Abstract: A study of acute lung injury reveals the involvement of transcription factor HIF1A in lung protection, where normoxic HIF1A stabilization functions to control alveolar epithelial glucose metabolism.

Cited by 145 publications

References 102 publications

Hypoxia-Inducible Factor Prolyl 4-Hydroxylase-2 Inhibition Protects Against Development of Atherosclerosis

Hypoxia-Inducible Factor Prolyl 4-Hydroxylase-2 Inhibition Protects Against Development of Atherosclerosis

Antihypoxic Potentiation of Standard Therapy for Experimental Colorectal Liver Metastasis through Myo-Inositol Trispyrophosphate

Altered Hypoxic–Adenosine Axis and Metabolism in Group III Pulmonary Hypertension

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