The PHD1 oxygen sensor in health and disease

Kennel, Kilian B; Burmeister, Julius; Schneider, Martin; Taylor, Cormac T.

doi:10.1113/jp275327

Cited by 26 publications

(20 citation statements)

References 111 publications

(140 reference statements)

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“…Historically, a variety of acute and chronic O 2 ‐sensing mechanisms have been proposed. These include increases, or paradoxically decreases, in reactive oxygen species (ROS), activation or inactivation of metabolites, for example, nitric oxide, prostanoids, etc, AMP‐activated protein kinase, ion channels, Na,K ATPase, haeme and other proteins and the hypoxia inducible factors …”

Section: Introductionmentioning

confidence: 99%

Extended hypoxia‐mediated H₂S production provides for long‐term oxygen sensing

et al. 2019

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Aim Numerous studies have shown that H2S serves as an acute oxygen sensor in a variety of cells. We hypothesize that H2S also serves in extended oxygen sensing. Methods Here, we compare the effects of extended exposure (24‐48 hours) to varying O2 tensions on H2S and polysulphide metabolism in human embryonic kidney (HEK 293), human adenocarcinomic alveolar basal epithelial (A549), human colon cancer (HTC116), bovine pulmonary artery smooth muscle, human umbilical‐derived mesenchymal stromal (stem) cells and porcine tracheal epithelium (PTE) using sulphur‐specific fluorophores and fluorometry or confocal microscopy. Results All cells continuously produced H2S in 21% O2 and H2S production was increased at lower O2 tensions. Decreasing O2 from 21% to 10%, 5% and 1% O2 progressively increased H2S production in HEK293 cells and this was partially inhibited by a combination of inhibitors of H2S biosynthesis, aminooxyacetate, propargyl glycine and compound 3. Mitochondria appeared to be the source of much of this increase in HEK 293 cells. H2S production in all other cells and PTE increased when O2 was lowered from 21% to 5% except for HTC116 cells where 1% O2 was necessary to increase H2S, presumably reflecting the hypoxic environment in vivo. Polysulphides (H2Sn, where n = 2‐7), the key signalling metabolite of H2S also appeared to increase in many cells although this was often masked by high endogenous polysulphide concentrations. Conclusion These results show that cellular H2S is increased during extended hypoxia and they suggest this is a continuously active O2‐sensing mechanism in a variety of cells.

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Section: Introductionmentioning

confidence: 99%

Extended hypoxia‐mediated H₂S production provides for long‐term oxygen sensing

et al. 2019

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“…Further studies of transgenic animals have provided intriguing insights into the role of individual PHD enzymes during the development of chronic diseases. For example, PHD1-deficient mice are protected against colitis or liver pathologies such as biliary fibrosis or ischemia/reperfusion injury [21,22,23,24,25].…”

Section: Hif Hydroxylationmentioning

confidence: 99%

Protein Hydroxylation by Hypoxia-Inducible Factor (HIF) Hydroxylases: Unique or Ubiquitous?

Strowitzki

Cummins

Taylor

2019

Cells

164

146

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All metazoans that utilize molecular oxygen (O2) for metabolic purposes have the capacity to adapt to hypoxia, the condition that arises when O2 demand exceeds supply. This is mediated through activation of the hypoxia-inducible factor (HIF) pathway. At physiological oxygen levels (normoxia), HIF-prolyl hydroxylases (PHDs) hydroxylate proline residues on HIF-α subunits leading to their destabilization by promoting ubiquitination by the von-Hippel Lindau (VHL) ubiquitin ligase and subsequent proteasomal degradation. HIF-α transactivation is also repressed in an O2-dependent way due to asparaginyl hydroxylation by the factor-inhibiting HIF (FIH). In hypoxia, the O2-dependent hydroxylation of HIF-α subunits by PHDs and FIH is reduced, resulting in HIF-α accumulation, dimerization with HIF-β and migration into the nucleus to induce an adaptive transcriptional response. Although HIFs are the canonical substrates for PHD- and FIH-mediated protein hydroxylation, increasing evidence indicates that these hydroxylases may also have alternative targets. In addition to PHD-conferred alterations in protein stability, there is now evidence that hydroxylation can affect protein activity and protein/protein interactions for alternative substrates. PHDs can be pharmacologically inhibited by a new class of drugs termed prolyl hydroxylase inhibitors which have recently been approved for the treatment of anemia associated with chronic kidney disease. The identification of alternative targets of HIF hydroxylases is important in order to fully elucidate the pharmacology of hydroxylase inhibitors (PHI). Despite significant technical advances, screening, detection and verification of alternative functional targets for PHDs and FIH remain challenging. In this review, we discuss recently proposed non-HIF targets for PHDs and FIH and provide an overview of the techniques used to identify these.

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“…In general, HIF-P4H-2 has been reported to be quite ubiquitously expressed, being the predominant HIF-P4H isoform in most tissues studied, for example in the heart, brain, liver, skeletal muscle and kidney, while it was detected only at low levels in the lung [ 15 , 16 , 17 ]. HIF-P4H-1 has been postulated to be the only isoform expressed in the testes [ 15 , 18 ], although another study demonstrated an abundance of all three isoforms in this tissue [ 19 ]. Highest HIF-P4H-3 expression has been detected in the heart [ 15 ] and HIF-P4H-3 seems to be particularly strongly expressed in epithelial cells of various tissues [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Expression and Roles of Individual HIF Prolyl 4-Hydroxylase Isoenzymes in the Regulation of the Hypoxia Response Pathway along the Murine Gastrointestinal Epithelium

Dengler

Sova

Salo

et al. 2021

IJMS

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The HIF prolyl 4-hydroxylases (HIF-P4H) control hypoxia-inducible factor (HIF), a powerful mechanism regulating cellular adaptation to decreased oxygenation. The gastrointestinal epithelium subsists in “physiological hypoxia” and should therefore have an especially well-designed control over this adaptation. Thus, we assessed the absolute mRNA expression levels of the HIF pathway components, Hif1a, HIF2a, Hif-p4h-1, 2 and 3 and factor inhibiting HIF (Fih1) in murine jejunum, caecum and colon epithelium using droplet digital PCR. We found a higher expression of all these genes towards the distal end of the gastrointestinal tract. We detected mRNA for Hif-p4h-1, 2 and 3 in all parts of the gastrointestinal tract. Hif-p4h-2 had significantly higher expression levels compared to Hif-p4h-1 and 3 in colon and caecum epithelium. To test the roles each HIF-P4H isoform plays in the gut epithelium, we measured the gene expression of classical HIF target genes in Hif-p4h-1−/−, Hif-p4h-2 hypomorph and Hif-p4h-3−/− mice. Only Hif-p4h-2 hypomorphism led to an upregulation of HIF target genes, confirming a predominant role of HIF-P4H-2. However, the abundance of Hif-p4h-1 and 3 expression in the gastrointestinal epithelium implies that these isoforms may have specific functions as well. Thus, the development of selective inhibitors might be useful for diverging therapeutic needs.

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The PHD1 oxygen sensor in health and disease

Cited by 26 publications

References 111 publications

Extended hypoxia‐mediated H₂S production provides for long‐term oxygen sensing

Extended hypoxia‐mediated H₂S production provides for long‐term oxygen sensing

Protein Hydroxylation by Hypoxia-Inducible Factor (HIF) Hydroxylases: Unique or Ubiquitous?

Expression and Roles of Individual HIF Prolyl 4-Hydroxylase Isoenzymes in the Regulation of the Hypoxia Response Pathway along the Murine Gastrointestinal Epithelium

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The PHD1 oxygen sensor in health and disease

Cited by 26 publications

References 111 publications

Extended hypoxia‐mediated H2S production provides for long‐term oxygen sensing

Extended hypoxia‐mediated H2S production provides for long‐term oxygen sensing

Protein Hydroxylation by Hypoxia-Inducible Factor (HIF) Hydroxylases: Unique or Ubiquitous?

Expression and Roles of Individual HIF Prolyl 4-Hydroxylase Isoenzymes in the Regulation of the Hypoxia Response Pathway along the Murine Gastrointestinal Epithelium

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Extended hypoxia‐mediated H₂S production provides for long‐term oxygen sensing

Extended hypoxia‐mediated H₂S production provides for long‐term oxygen sensing