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Deficiency of myeloid PHD proteins aggravates atherogenesis via macrophage apoptosis and paracrine fibrotic signaling [bulk RNA-seq]

ABSTRACT: Atherosclerotic plaque hypoxia is detrimental for macrophage function. Prolyl hydroxylases (PHDs) initiate cellular responses to hypoxia and may therefore govern macrophage function in plaque hypoxia. PHD inhibitors are clinically investigated to treat anemia in patients with chronic kidney disease, but the consequences for cardiovascular disease are not clear. Hence, we studied the influence of myeloid specific PHD deficiency on atherosclerotic plaque development and stability.

ORGANISM(S): Mus musculus

PROVIDER: GSE150088 | GEO | 2022/03/30

REPOSITORIES: GEO

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Deficiency of myeloid PHD proteins aggravates atherogenesis via macrophage apoptosis and paracrine fibrotic signaling [single-cell RNA-seq]

Project description:Atherosclerotic plaque hypoxia is detrimental for macrophage function. Prolyl hydroxylases (PHDs) initiate cellular responses to hypoxia and may therefore govern macrophage function in plaque hypoxia. PHD inhibitors are clinically investigated to treat anemia in patients with chronic kidney disease, but the consequences for cardiovascular disease are not clear. Hence, we studied the influence of myeloid specific PHD deficiency on atherosclerotic plaque development and stability.

2022-03-30 | GSE150089 | GEO

Tuning the transcriptional response to hypoxia through HIF prolyl- and asparaginyl-hydroxylase inhibition:Sequencing Data

Project description:The hypoxia inducible factor (HIF) system orchestrates cellular responses to hypoxia in animals. HIF is an /-heterodimeric transcription factor that regulates the expression of hundreds of genes in a context dependent manner. A hypoxia-sensing component of the HIF system involves oxygen-dependent catalysis by the HIF hydroxylases; in humans there are three HIF prolyl hydroxylases (PHD1-3) and an asparaginyl hydroxylase (FIH). PHD catalysis regulates HIF levels and FIH catalysis regulates HIF activity. How differences in HIF hydroxylation status relate to variations in the induction of HIF target gene transcription is unknown. We report studies using small molecule inhibitors of the HIF hydroxylases to investigate the extent to which HIF target gene upregulation is induced by reduced PHD catalysis. The results reveal substantial differences in the role of prolyl- and asparaginyl-hydroxylation in regulating hypoxia responsive genes in cells. Selective PHD inhibitors with different structural scaffolds behave similarly. However, under the tested conditions, a broad-spectrum 2OG dioxygenase inhibitor is a better mimic of the transcriptional response to hypoxia than the selective PHD inhibitors, consistent with an important role for FIH in the hypoxic transcriptional response. Indeed, combined application of selective PHD and FIH inhibitors resulted in transcriptional induction of a subset of genes that were not fully responsive to PHD inhibition alone. Thus, for the therapeutic regulation of HIF target genes, it is important to consider both PHD and FIH activity, and in the case of some sets of target genes, simultaneous inhibition of the PHDs and FIH catalysis may be preferable.

2016-10-25 | E-MTAB-4264 | biostudies-arrayexpress

Tuning the transcriptional response to hypoxia through HIF prolyl- and asparaginyl-hydroxylase inhibition: Microarray data

Project description:The hypoxia inducible factor (HIF) system orchestrates cellular responses to hypoxia in animals. HIF is an Î±/Î²-heterodimeric transcription factor that regulates the expression of hundreds of genes in a context dependent manner. A hypoxia-sensing component of the HIF system involves oxygen-dependent catalysis by the HIF hydroxylases; in humans there are three HIF prolyl hydroxylases (PHD1-3) and an asparaginyl hydroxylase (FIH). PHD catalysis regulates HIFÎ± levels and FIH catalysis regulates HIF activity. How differences in HIFÎ± hydroxylation status relate to variations in the induction of HIF target gene transcription is unknown. We report studies using small molecule inhibitors of the HIF hydroxylases to investigate the extent to which HIF target gene upregulation is induced by reduced PHD catalysis. The results reveal substantial differences in the role of prolyl- and asparaginyl-hydroxylation in regulating hypoxia responsive genes in cells. Selective PHD inhibitors with different structural scaffolds behave similarly. However, under the tested conditions, a broad-spectrum 2OG dioxygenase inhibitor is a better mimic of the transcriptional response to hypoxia than the selective PHD inhibitors, consistent with an important role for FIH in the hypoxic transcriptional response. Indeed, combined application of selective PHD and FIH inhibitors resulted in transcriptional induction of a subset of genes that were not fully responsive to PHD inhibition alone. Thus, for the therapeutic regulation of HIF target genes, it is important to consider both PHD and FIH activity, and in the case of some sets of target genes, simultaneous inhibition of the PHDs and FIH catalysis may be preferable.

2016-08-31 | E-MTAB-4300 | biostudies-arrayexpress

Hypoxia inducible factor prolyl hydroxylase inhibition compromises development and progression of acute myeloid leukaemia

Project description:Acute myeloid leukaemia (AML) is a largely incurable haematological disease, for which new efficient therapeutic strategies are urgently needed. While leukaemogenesis occurs under hypoxic conditions of the bone marrow, the therapeutic tractability of the hypoxia inducible factor (HIF) system in AML is elusive. Given that inactivation of HIF-1α and HIF-2α promotes leukaemic transformation, a possible therapeutic strategy for AML treatment is to constitutively stabilise HIF- α proteins. This can be achieved by targeting the HIF-prolyl hydroxylases (PHDs), the catalysis of which promotes HIF-1α and HIF-2α degradation. Here, we demonstrate that genetic inactivation of Phd1 or Phd2 compromises initiation and progression of AML, without impacting normal haematopoiesis, thus implying the immense therapeutic potential of targeting PHDs in AML. To pharmacologically inactivate PHDs, we employed clinical grade PHD inhibitors as well as a new selective PHD inhibitor (IOX5), which stabilises HIF-α through a novel mechanism of action. Pharmacological PHD inhibition compromises AML cells in a HIF-α dependent manner to disable pro-leukaemogenic pathways in AML cells, re-program their metabolism, and induce cell death, at least in part via pro-apoptotic BNIP3. Importantly, concurrent inhibition of anti-apoptotic BCL-2 by clinically used Venetoclax potentiates the anti-leukaemic effect of PHD inhibition. Thus PHD inhibition with consequent HIF-α stabilisation is a promising new non-toxic strategy for AML treatment.

2024-02-14 | GSE232644 | GEO

Deficiency of myeloid PHD proteins aggravates atherogenesis via macrophage apoptosis and paracrine fibrotic signaling

Project description:Deficiency of myeloid PHD proteins aggravates atherogenesis via macrophage apoptosis and paracrine fibrotic signaling

| PRJNA631056 | ENA

Deficiency of myeloid PHD proteins aggravates atherogenesis via macrophage apoptosis and paracrine fibrotic signaling [bulk RNA-seq]

Project description:Deficiency of myeloid PHD proteins aggravates atherogenesis via macrophage apoptosis and paracrine fibrotic signaling [bulk RNA-seq]

| PRJNA631057 | ENA

Deficiency of myeloid PHD proteins aggravates atherogenesis via macrophage apoptosis and paracrine fibrotic signaling [single-cell RNA-seq]

Project description:Deficiency of myeloid PHD proteins aggravates atherogenesis via macrophage apoptosis and paracrine fibrotic signaling [single-cell RNA-seq]

| PRJNA631058 | ENA

Deficiency of myeloid PHD proteins aggravates atherogenesis via macrophage apoptosis and paracrine fibrotic signaling

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-03-30 | GSE150090 | GEO

Adaptaquin is an inhibitor of oxygen-sensing prolyl-hydroxylase domain enzymes that abrogates ATF4-dependent death and improves outcomes from brain hemorrhage

Project description:Disability or death secondary to intracerebral hemorrhage (ICH) is attributed to blood lysis, liberation of iron and generation of oxidative stress. Iron chelators bind free iron and prevent neuronal death induced by oxidative stress and disability due to ICH, but the mechanisms remain unclear. Here we show that the hypoxia-inducible factor prolylhydroxylase (HIF PHD) family of iron-dependent oxygen sensors is an effector of iron chelation in abrogating ICH-induced death. Molecular reduction of the three HIF PHD isoforms in mouse striatum improves functional recovery following ICH. A low molecular weight, hydroxyquinoline inhibitor of the HIF PHDs, which we call adaptaquin, reduces neuronal death and behavioral deficits following ICH in distinct rodent models. Unexpectedly, adaptaquin protects from oxidative death by suppressing ATF4- dependent prodeath gene expression rather than by activating a HIF-dependent prosurvival pathway. Adaptaquin treated neurons

2016-03-01 | E-GEOD-75048 | biostudies-arrayexpress

Gene expression profiling of human atherosclerotic plaque

Project description:This SuperSeries is composed of the following subset Series: GSE23303: Gene expression profiling of human atherosclerotic plaque: Laser capture microscopy of smooth muscle cells and macrophages GSE23304: Gene expression profiling of human atherosclerotic plaque: 101 peripheral plaques GSE24495: Gene expression profiling of human atherosclerotic plaque: Carotid plaque GSE24702: Gene expression profiling of human atherosclerotic plaque: 290 peripheral plaques Refer to individual Series

2011-09-30 | E-GEOD-23314 | biostudies-arrayexpress