title: Transmembrane prolyl 4-hydroxylase is a fourth prolyl 4-hydroxylase regulating EPO production and erythropoiesis.
abstract: An endoplasmic reticulum transmembrane prolyl 4-hydroxylase (P4H-TM) is able to hydroxylate the α subunit of the hypoxia-inducible factor (HIF) in vitro and in cultured cells, but nothing is known about its roles in mammalian erythropoiesis. We studied such roles here by administering a HIF-P4H inhibitor, FG-4497, to P4h-tm(-/-) mice. This caused larger increases in serum Epo concentration and kidney but not liver Hif-1α and Hif-2α protein and Epo mRNA levels than in wild-type mice, while the liver Hepcidin mRNA level was lower in the P4h-tm(-/-) mice than in the wild-type. Similar, but not identical, differences were also seen between FG-4497-treated Hif-p4h-2 hypomorphic (Hif-p4h-2(gt/gt)) and Hif-p4h-3(-/-) mice versus wild-type mice. FG-4497 administration increased hemoglobin and hematocrit values similarly in the P4h-tm(-/-) and wild-type mice, but caused higher increases in both values in the Hif-p4h-2(gt/gt) mice and in hematocrit value in the Hif-p4h-3(-/-) mice than in the wild-type. Hif-p4h-2(gt/gt)/P4h-tm(-/-) double gene-modified mice nevertheless had increased hemoglobin and hematocrit values without any FG-4497 administration, although no such abnormalities were seen in the Hif-p4h-2(gt/gt) or P4h-tm(-/-) mice. Our data thus indicate that P4H-TM plays a role in the regulation of EPO production, hepcidin expression, and erythropoiesis.
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu, Finland.
authors.forename: Anu
authors.initials: A
authors.lastname: Laitala
authors.forename: Ellinoora
authors.initials: E
authors.lastname: Aro
authors.forename: Gail
authors.initials: G
authors.lastname: Walkinshaw
authors.forename: Joni M
authors.initials: JM
authors.lastname: Mäki
authors.forename: Maarit
authors.initials: M
authors.lastname: Rossi
authors.forename: Minna
authors.initials: M
authors.lastname: Heikkilä
authors.forename: Eeva-Riitta
authors.initials: ER
authors.lastname: Savolainen
authors.forename: Michael
authors.initials: M
authors.lastname: Arend
authors.forename: Kari I
authors.initials: KI
authors.lastname: Kivirikko
authors.forename: Peppi
authors.initials: P
authors.lastname: Koivunen
authors.forename: Johanna
authors.initials: J
authors.lastname: Myllyharju
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D015153:Blotting, Western; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D004920:Erythropoiesis / Q000502:physiology*; D004921:Erythropoietin / Q000097:blood*; D005260:Female; D006400:Hematocrit; D006454:Hemoglobins / Q000378:metabolism; D064451:Hepcidins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D023181:Antimicrobial Cationic Peptides; D004791:Enzyme Inhibitors; C579599:Hamp protein, mouse; D006454:Hemoglobins; D064451:Hepcidins; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D004921:Erythropoietin; D011393:Procollagen-Proline Dioxygenase