title: Modulation of hepcidin production during hypoxia-induced erythropoiesis in humans in vivo: data from the HIGHCARE project.
abstract: Iron is tightly connected to oxygen homeostasis and erythropoiesis. Our aim was to better understand how hypoxia regulates iron acquisition for erythropoiesis in humans, a topic relevant to common hypoxia-related disorders. Forty-seven healthy volunteers participated in the HIGHCARE project. Blood samples were collected at sea level and after acute and chronic exposure to high altitude (3400-5400 m above sea level). We investigated the modifications in hematocrit, serum iron indices, erythropoietin, markers of erythropoietic activity, interleukin-6, and serum hepcidin. Hepcidin decreased within 40 hours after acute hypoxia exposure (P < .05) at 3400 m, reaching the lowest level at 5400 m (80% reduction). Erythropoietin significantly increased (P < .001) within 16 hours after hypoxia exposure followed by a marked erythropoietic response supported by the increased iron supply. Growth differentiation factor-15 progressively increased during the study period. Serum ferritin showed a very rapid decrease, suggesting the existence of hypoxia-dependent mechanism(s) regulating storage iron mobilization. The strong correlation between serum ferritin and hepcidin at each point during the study indicates that iron itself or the kinetics of iron use in response to hypoxia may signal hepcidin down-regulation. The combined and significant changes in other variables probably contribute to the suppression of hepcidin in this setting.
authors.affiliation: Department of Clinical Medicine and Prevention, University of Milano-Bicocca and S. Gerardo Hospital, Monza, Italy. alberto.piperno@unimib.it
authors.forename: Alberto
authors.initials: A
authors.lastname: Piperno
authors.forename: Stefania
authors.initials: S
authors.lastname: Galimberti
authors.forename: Raffaella
authors.initials: R
authors.lastname: Mariani
authors.forename: Sara
authors.initials: S
authors.lastname: Pelucchi
authors.forename: Giulia
authors.initials: G
authors.lastname: Ravasi
authors.forename: Carolina
authors.initials: C
authors.lastname: Lombardi
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Bilo
authors.forename: Miriam
authors.initials: M
authors.lastname: Revera
authors.forename: Andrea
authors.initials: A
authors.lastname: Giuliano
authors.forename: Andrea
authors.initials: A
authors.lastname: Faini
authors.forename: Veronica
authors.initials: V
authors.lastname: Mainini
authors.forename: Mark
authors.initials: M
authors.lastname: Westerman
authors.forename: Tomas
authors.initials: T
authors.lastname: Ganz
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Valsecchi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mancia
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Parati
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis / Q000097:blood*; D015536:Down-Regulation; D004920:Erythropoiesis / Q000502:physiology*; D004921:Erythropoietin / Q000096:biosynthesis / Q000097:blood; D005260:Female; D005293:Ferritins / Q000097:blood; D006400:Hematocrit; D064451:Hepcidins; D006801:Humans; D000860:Hypoxia / Q000097:blood* / Q000503:physiopathology; D007501:Iron / Q000378:metabolism*; D008297:Male
chemical_list: D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; D064451:Hepcidins; D004921:Erythropoietin; D005293:Ferritins; D007501:Iron