title: Heme-bound iron activates placenta growth factor in erythroid cells via erythroid Krüppel-like factor.
abstract: In adults with sickle cell disease (SCD), markers of iron burden are associated with excessive production of the angiogenic protein placenta growth factor (PlGF) and high estimated pulmonary artery pressure. Enforced PlGF expression in mice stimulates production of the potent vasoconstrictor endothelin-1, producing pulmonary hypertension. We now demonstrate heme-bound iron (hemin) induces PlGF mRNA >200-fold in a dose- and time-dependent fashion. In murine and human erythroid cells, expression of erythroid Krüppel-like factor (EKLF) precedes PlGF, and its enforced expression in human erythroid progenitor cells induces PlGF mRNA. Hemin-induced expression of PlGF is abolished in EKLF-deficient murine erythroid cells but rescued by conditional expression of EKLF. Chromatin immunoprecipitation reveals that EKLF binds to the PlGF promoter region. SCD patients show higher level expression of both EKLF and PlGF mRNA in circulating blood cells, and markers of iron overload are associated with high PlGF and early mortality. Finally, PlGF association with iron burden generalizes to other human diseases of iron overload. Our results demonstrate a specific mechanistic pathway induced by excess iron that is linked in humans with SCD and in mice to markers of vasculopathy and pulmonary hypertension. These trials were registered at www.clinicaltrials.gov as #NCT00007150, #NCT00023296, #NCT00081523, and #NCT00352430.
authors.affiliation: National Heart, Lung and Blood Institute.
authors.forename: Xunde
authors.initials: X
authors.lastname: Wang
authors.affiliation: National Heart, Lung and Blood Institute.
authors.forename: Laurel
authors.initials: L
authors.lastname: Mendelsohn
authors.affiliation: National Institutes of Diabetes and Digestive and Kidney Diseases.
authors.forename: Heather
authors.initials: H
authors.lastname: Rogers
authors.affiliation: Clinical Center, and.
authors.forename: Susan
authors.initials: S
authors.lastname: Leitman
authors.affiliation: National Institute on Aging, National Institutes of Health, Bethesda, MD;
authors.forename: Nalini
authors.initials: N
authors.lastname: Raghavachari
authors.affiliation: National Heart, Lung and Blood Institute.
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Clinical Center, and.
authors.forename: Yu Ying
authors.initials: YY
authors.lastname: Yau
authors.affiliation: Mater Medical Research Institute, Mater Hospital, Brisbane, QLD, Australia; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Tallack
authors.affiliation: Mater Medical Research Institute, Mater Hospital, Brisbane, QLD, Australia; and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Perkins
authors.affiliation: National Heart, Lung and Blood Institute.
authors.forename: James G
authors.initials: JG
authors.lastname: Taylor
authors.affiliation: National Institutes of Diabetes and Digestive and Kidney Diseases.
authors.forename: Constance Tom
authors.initials: CT
authors.lastname: Noguchi
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, and the Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Gregory J
authors.identifier: http://orcid.org/0000-0003-4465-3217
authors.initials: GJ
authors.lastname: Kato
mesh_terms: D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood* / Q000150:complications / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation; D041905:Erythroid Cells / Q000378:metabolism* / Q000473:pathology; D006418:Heme / Q000378:metabolism*; D006427:Hemin / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000209:etiology; D007501:Iron / Q000097:blood*; D019190:Iron Overload / Q000097:blood / Q000235:genetics; D020014:K562 Cells; D051741:Kruppel-Like Transcription Factors / Q000097:blood* / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000097:blood* / Q000235:genetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics
chemical_list: D051741:Kruppel-Like Transcription Factors; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D012333:RNA, Messenger; C080774:erythroid Kruppel-like factor; D000072483:Placenta Growth Factor; D006418:Heme; D006427:Hemin; D007501:Iron