title: Prolyl-4-hydroxylase domain 3 (PHD3) is a critical terminator for cell survival of macrophages under stress conditions.
abstract: On a molecular level, cells sense changes in oxygen availability through the PHDs, which regulate the protein stability of the α-subunit of the transcription factor HIF. Especially, PHD3 has been additionally associated with apoptotic cell death. We hypothesized that PHD3 plays a role in cell-fate decisions in macrophages. Therefore, myeloid-specific PHD3(-/-) mice were created and analyzed. PHD3(-/-) BMDM showed no altered HIF-1α or HIF-2α stabilization or increased HIF target gene expression in normoxia or hypoxia. Macrophage M1 and M2 polarization was unchanged likewise. Compared with macrophages from WT littermates, PHD3(-/-) BMDM exhibited a significant reduction in TUNEL-positive cells after serum withdrawal or treatment with stauro and SNAP. Under the same conditions, PHD3(-/-) BMDM also showed less Annexin V staining, which is representative for membrane disruption, and indicated a reduced early apoptosis. In an unbiased transcriptome screen, we found that Angptl2 expression was reduced in PHD3(-/-) BMDM under stress conditions. Addition of rAngptl2 rescued the antiapoptotic phenotype, demonstrating that it is involved in the PHD3-mediated response toward apoptotic stimuli in macrophages.
authors.affiliation: Institute of Cardiovascular Physiology, University Medical Center, Georg August University Göttingen, Germany; and.
authors.forename: Lija
authors.initials: L
authors.lastname: Swain
authors.affiliation: Institute of Cardiovascular Physiology, University Medical Center, Georg August University Göttingen, Germany; and.
authors.forename: Marieke
authors.initials: M
authors.lastname: Wottawa
authors.affiliation: Institute of Cardiovascular Physiology, University Medical Center, Georg August University Göttingen, Germany; and.
authors.forename: Annette
authors.initials: A
authors.lastname: Hillemann
authors.affiliation: Institute of Cardiovascular Physiology, University Medical Center, Georg August University Göttingen, Germany; and.
authors.forename: Angelika
authors.initials: A
authors.lastname: Beneke
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Japan.
authors.forename: Haruki
authors.initials: H
authors.lastname: Odagiri
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Japan.
authors.forename: Kazutoyo
authors.initials: K
authors.lastname: Terada
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Japan.
authors.forename: Motoyoshi
authors.initials: M
authors.lastname: Endo
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oike
authors.affiliation: Institute of Cardiovascular Physiology, University Medical Center, Georg August University Göttingen, Germany; and.
authors.forename: Katja
authors.initials: K
authors.lastname: Farhat
authors.affiliation: Institute of Cardiovascular Physiology, University Medical Center, Georg August University Göttingen, Germany; and doerthe.katschinski@med.uni-goettingen.de.
authors.forename: Dörthe M
authors.initials: DM
authors.lastname: Katschinski
mesh_terms: D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology; D015687:Cell Hypoxia; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006900:Hydroxylation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000201:enzymology; D016328:NF-kappa B / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology; D014158:Transcription, Genetic; D059467:Transcriptome; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D011393:Procollagen-Proline Dioxygenase; D011993:Recombinant Fusion Proteins; D026423:S-Nitroso-N-Acetylpenicillamine; D019311:Staurosporine; D000099162:Endothelial PAS Domain-Containing Protein 1; C485792:ANGPTL2 protein, human; C485793:Angptl2 protein, mouse; C497443:Hif1a protein, mouse; C522722:PHD3 protein, mouse
keywords: HIF; angiopoietin-like protein; hypoxia; oxygen sensing