Hypoxic up-regulation of erythroid 5-aminolevulinate synthase

Höfer, Thomas; Wenger, Roland H.; Kramer, Marianne F.; Ferreira, Glória C.; Gassmann, Max

doi:10.1182/blood-2002-03-0773

Cited by 58 publications

(49 citation statements)

References 24 publications

(25 reference statements)

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“…These observations are consistent with other studies showing that, under hypoxia, hypoxia-inducible factor-1␣ (HIF-1␣) binding to hypoxia response elements in the ferrochelatase gene promoter is likely to be upregulating FECH expression and activity (28,35). The rate-limiting step in heme biosynthesis, ␦-aminolevulinic acid synthase, has also been reported to be upregulated under hypoxia in erythroid cells, but this increase does not appear to be mediated by HIF-1␣ (22). We hypothesize that this overall induction of the heme biosynthesis pathway by hypoxia could be part of an adaptation mechanism in which the pulmonary vasculature responds to hypoxia-induced stress by upregulating the heme biosynthesis pathway to meet the heme requirements for the assembly of hemo-proteins, including cytochrome c oxidase (complex IV in the mitochondrial electron transport system) and perhaps sGC.…”

Section: Et)supporting

confidence: 81%

Heme biosynthesis modulation via δ-aminolevulinic acid administration attenuates chronic hypoxia-induced pulmonary hypertension

Alhawaj

Patel

Kelly

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Alhawaj R, Patel D, Kelly MR, Sun D, Wolin MS. Heme biosynthesis modulation via ␦-aminolevulinic acid administration attenuates chronic hypoxia-induced pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 308: L719 -L728, 2015. First published February 6, 2015 doi:10.1152/ajplung.00155.2014.-This study examines how heme biosynthesis modulation with ␦-aminolevulinic acid (ALA) potentially functions to prevent 21-day hypoxia (10% oxygen)-induced pulmonary hypertension in mice and the effects of 24-h organoid culture with bovine pulmonary arteries (BPA) with the hypoxia and pulmonary hypertension mediator endothelin-1 (ET-1), with a focus on changes in superoxide and regulation of micro-RNA 204 (miR204) expression by src kinase phosphorylation of signal transducer and activator of transcription-3 (STAT3). The treatment of mice with ALA attenuated pulmonary hypertension (assessed through echo Doppler flow of the pulmonary valve, and direct measurements of right ventricular systolic pressure and right ventricular hypertrophy), increases in pulmonary arterial superoxide (detected by lucigenin), and decreases in lung miR204 and mitochondrial superoxide dismutase (SOD2) expression. ALA treatment of BPA attenuated ET-1-induced increases in mitochondrial superoxide (detected by MitoSox), STAT3 phosphorylation, and decreases in miR204 and SOD2 expression. Because ALA increases BPA protoporphyrin IX (a stimulator of guanylate cyclase) and cGMP-mediated protein kinase G (PKG) activity, the effects of the PKG activator 8-bromo-cGMP were examined and found to also attenuate the ET-1-induced increase in superoxide. ET-1 increased superoxide production and the detection of protoporphyrin IX fluorescence, suggesting oxidant conditions might impair heme biosynthesis by ferrochelatase. However, chronic hypoxia actually increased ferrochelatase activity in mouse pulmonary arteries. Thus, a reversal of factors increasing mitochondrial superoxide and oxidant effects that potentially influence remodeling signaling related to miR204 expression and perhaps iron availability needed for the biosynthesis of heme by the ferrochelatase reaction could be factors in the beneficial actions of ALA in pulmonary hypertension. endothelin; ferrochelatase; guanylate cyclase; micro-RNA 204; superoxide CHRONIC HYPOXIA IS AN IMPORTANT factor in the development of pulmonary hypertension in diseases such as chronic obstructive pulmonary disease (COPD), sleep apnea, and mountain sickness (10,20). It is thought to promote pulmonary hypertension development through persistent pulmonary vasoconstriction and vascular remodeling (31). There is substantial evidence for increases in the generation of reactive oxygen species from sources including Nox oxidases and mitochondria having important roles in the development and/or progression of pulmonary hypertension caused by chronic hypoxia and other stimuli of this disease process (7,15,18,27,30). Pulmonary arterial generation of nitric oxide (NO) is normally thought to oppose this process of vasoconstriction ...

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Section: Et)supporting

confidence: 81%

Heme biosynthesis modulation via δ-aminolevulinic acid administration attenuates chronic hypoxia-induced pulmonary hypertension

Alhawaj

Patel

Kelly

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…In line with such a cell-type specificity, hypoxic upregulation of VEGF transcription, commonly referred to as a HIF-dependent process, was shown to be HIF-1-independent in colon cancer cells (Mizukami et al, 2004). Moreover, hypoxia-induced but HIF-independent upregulation of erythroid 5-aminolevulinate synthase (Hofer et al, 2003) suggests the existence of different mechanisms for this process in given cell types.…”

Section: Discussionmentioning

confidence: 84%

NF-κB contributes to transcription of placenta growth factor and interacts with metal responsive transcription factor-1 in hypoxic human cells

Cramer

Nagy

Murphy

et al. 2005

Biological Chemistry

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Placenta growth factor (PlGF) is a member of the vascular endothelial growth factor family of cytokines that control vascular and lymphatic endothelium development. It has been implicated in promoting angiogenesis in pathological conditions via signaling to vascular endothelial growth factor receptor-1. PlGF expression is induced by hypoxia and proinflammatory stimuli. Metal responsive transcription factor 1 (MTF-1) was shown to take part in the hypoxic induction of PlGF in Ras-transformed mouse embryonic fibroblasts. Here we report that PlGF expression is also controlled by NF-kB. We identified several putative binding sites for NF-kB in the PlGF promoter/enhancer region by sequence analyses, and show binding and transcriptional activity of NF-kB p65 at these sites. Expression of NF-kB p65 from a plasmid vector in HEK293 cells caused a substantial increase of PlGF transcript levels. Furthermore, we found that hypoxic conditions induce nuclear translocation and interaction of MTF-1 and NF-kB p65 proteins, suggesting a role for this complex in hypoxia-induced transcription of PlGF.

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“…The erythroid-specific 5-aminolevulinate synthase (ALAS2) is critically involved in heme synthesis and the ALAS2 mRNA is hypoxically induced in a HIF-independent manner [105]. A LXXLAP motif has been identified in ALAS2.…”

Section: Alas2mentioning

confidence: 99%

HIF Prolyl-4-hydroxylase Interacting Proteins: Consequences for Drug Targeting

Wenger¹,

Camenisch²,

Stiehl³

et al. 2009

CPD

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Protein stability of hypoxia-inducible factor (HIF) subunits is regulated by the oxygen-sensing prolyl-4-hydroxylase domain (PHD) enzymes. Under oxygen-limited conditions, HIF subunits are stabilized and form active HIF transcription factors that induce a large number of genes involved in adaptation to hypoxic conditions with physiological implications for erythropoiesis, angiogenesis, cardiovascular function and cellular metabolism. Oxygen-sensing is regulated by the co-substrate-dependent activity and hypoxia-inducible abundance of the PHD enzymes which trigger HIF stability even under low oxygen conditions. Because HIF itself is notoriously reluctant to the development of antagonists, an increase in PHD activity would offer an interesting alternative to the development of drugs that interfere specifically with the HIF signalling pathway. Interestingly, among the recently discovered PHD interacting proteins were not only novel downstream targets but also upstream regulators of PHDs. Their PHD isoform-specific interaction offers the possibility to target distinct PHD isoforms and their non-identical downstream signalling pathways. This review summarizes our current knowledge on PHD interacting proteins, including upstream regulators, chaperonins, scaffolding proteins, and novel downstream transcription factors.

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Hypoxic up-regulation of erythroid 5-aminolevulinate synthase

Cited by 58 publications

References 24 publications

Heme biosynthesis modulation via δ-aminolevulinic acid administration attenuates chronic hypoxia-induced pulmonary hypertension

Heme biosynthesis modulation via δ-aminolevulinic acid administration attenuates chronic hypoxia-induced pulmonary hypertension

NF-κB contributes to transcription of placenta growth factor and interacts with metal responsive transcription factor-1 in hypoxic human cells

HIF Prolyl-4-hydroxylase Interacting Proteins: Consequences for Drug Targeting

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