Regulation of ferrochelatase gene expression by hypoxia

Liu, Yunying L.; Ang, Sonny; Weigent, Douglas A.; Prchal, Josef T.; Bloomer, Joseph R.

doi:10.1016/j.lfs.2004.03.027

Cited by 54 publications

(29 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…6B). 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).…”

Section: Et)supporting

confidence: 91%

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

View full text Add to dashboard Cite

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 ...

show abstract

Section: Et)supporting

confidence: 91%

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

View full text Add to dashboard Cite

show abstract

“…CASP3, BCL2 and BAX [46]) and haem biosynthesis (e.g. PPOX, CPO and FECH [47]). Additionally, genes that may be affected or regulated by O 2 concentration were selected (e.g.…”

Section: Adaptation To Hyperoxic Conditions Significantly Enhances Bamentioning

confidence: 99%

Altered cellular redox homeostasis and redox responses under standard oxygen cell culture conditions versus physioxia

Ferguson

Smerdon

Harries

et al. 2018

Free Radical Biology and Medicine

View full text Add to dashboard Cite

In vivo, mammalian cells reside in an environment of 0.5-10% O 2 (depending on the tissue location within the body), whilst standard in vitro cell culture is carried out under room air. Little is known about the effects of this hyperoxic environment on treatment-induced oxidative stress, relative to a physiological oxygen environment. In the present study we investigated the effects of long-term culture under hyperoxia (air) on photodynamic treatment. Upon photodynamic irradiation, cells which had been cultured long-term under hyperoxia generated higher concentrations of mitochondrial reactive oxygen species, compared with cells in a physioxic (2% O 2 ) environment. However, there was no significant difference in viability between hyperoxic and physioxic cells. The expression of genes encoding key redox homeostasis proteins and the activity of key antioxidant enzymes was significantly higher after the long-term culture of hyperoxic cells compared with physioxic cells. The induction of antioxidant genes and increased antioxidant enzyme activity appear to contribute to the development of a phenotype that is resistant to oxidative stress-induced cellular damage and death when using standard cell culture conditions. The results from experiments using selective inhibitors suggested that the thioredoxin antioxidant system contributes to this phenotype. To avoid artefactual results, in vitro cellular responses should be studied in mammalian cells that have been cultured under physioxia. This investigation provides new insights into the effects of physioxic cell culture on a model of a clinically relevant photodynamic treatment and the associated cellular pathways.

show abstract

“…Hypoxia stimulates EPO receptor expression and regulates components of the hemoglobin synthesis pathway (26,52,84,91,167). It modulates the interaction of erythroid progenitors with other cell types, thereby affecting stem cell maintenance, lineage differentiation, and maturation.…”

Section: Hypoxic Regulation Of Iron Homeostasis and Bone Marrow Envirmentioning

confidence: 99%

Hypoxic regulation of erythropoiesis and iron metabolism

Haase

2010

American Journal of Physiology-Renal Physiology

277

217

View full text Add to dashboard Cite

Haase VH. Hypoxic regulation of erythropoiesis and iron metabolism. Am J Physiol Renal Physiol 299: F1-F13, 2010. First published May 5, 2010 doi:10.1152/ajprenal.00174.2010.-The kidney is a highly sensitive oxygen sensor and plays a central role in mediating the hypoxic induction of red blood cell production. Efforts to understand the molecular basis of oxygen-regulated erythropoiesis have led to the identification of erythropoietin (EPO), which is essential for normal erythropoiesis and to the purification of hypoxia-inducible factor (HIF), the transcription factor that regulates EPO synthesis and mediates cellular adaptation to hypoxia. Recent insights into the molecular mechanisms that control and integrate cellular and systemic erythropoiesis-promoting hypoxia responses and their potential as a therapeutic target for the treatment of renal anemia are discussed in this review.erythropoietin; hypoxia; hypoxia-inducible factors; iron; red blood cells ONE OF THE MOST EXTENSIVELY studied systemic adaptations to hypoxia is the stimulation of red blood cell (RBC) production. Over 100 years ago, Paul Bert and Denis Jourdanet observed the association between reduced atmospheric oxygen pressure and elevated RBC numbers in the blood of animals and humans (12, 13, 64). Francois-Gilbert Viault then demonstrated that ascent to a high altitude provided an acute and direct physiological stimulus for RBC production during his 1890 expedition to the Peruvian Andes by measuring the RBC increases in his own and the blood of his companions (156). It was the interest in understanding the physiological and molecular basis of this erythropoietic response that led to the discovery of erythropoietin (EPO) and that paved the way for the identification of the molecular machinery that senses oxygen and controls a wide spectrum of tissue-specific and systemic responses to hypoxia.The hypoxic induction of EPO serves as a paradigm of oxygen-dependent gene regulation, and the search for the transcription factor that mediates this induction led to the discovery of the hypoxia-inducible factor (HIF) as a key mediator of cellular adaptation to low oxygen. Recent experimental evidence suggests that HIF promotes erythropoiesis through coordinated cell type-specific hypoxia responses, which include increased EPO production in the kidney and liver, enhanced iron uptake and utilization, as well as changes in the bone marrow microenvironment that facilitate erythroid progenitor maturation and proliferation. Because of its central role in the hypoxic regulation of erythropoiesis, pharmacological targeting of the HIF oxygen-sensing pathway has the potential to become an effective, novel therapy in the treatment of anemia that is associated with inadequate EPO production.This review provides an overview of recent insights into the molecular mechanisms that underlie oxygen-dependent regulation of EPO synthesis, iron metabolism, and erythroid progenitor maturation and discusses their relevance to clinical disorders. Oxygen-Dependent Regulation of EPO ...

show abstract

Regulation of ferrochelatase gene expression by hypoxia

Cited by 54 publications

References 30 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

Altered cellular redox homeostasis and redox responses under standard oxygen cell culture conditions versus physioxia

Hypoxic regulation of erythropoiesis and iron metabolism

Contact Info

Product

Resources

About