title: Hypoxia-Inducible Factor 1α Is a Critical Downstream Mediator for Hypoxia-Induced Mitogenic Factor (FIZZ1/RELMα)-Induced Pulmonary Hypertension.
abstract: OBJECTIVE
  Pulmonary hypertension (PH) is characterized by progressive elevation of pulmonary vascular resistance, right ventricular failure, and ultimately death. We have shown that in rodents, hypoxia-induced mitogenic factor (HIMF; also known as FIZZ1 or resistin-like molecule-β) causes PH by initiating lung vascular inflammation. We hypothesized that hypoxia-inducible factor-1 (HIF-1) is a critical downstream signal mediator of HIMF during PH development.
  
  
  RESULTS
  In this study, we compared the degree of HIMF-induced pulmonary vascular remodeling and PH development in wild-type (HIF-1α(+/+)) and HIF-1α heterozygous null (HIF-1α(+/-)) mice. HIMF-induced PH was significantly diminished in HIF-1α(+/-) mice and was accompanied by a dysregulated vascular endothelial growth factor-A-vascular endothelial growth factor receptor 2 pathway. HIF-1α was critical for bone marrow-derived cell migration and vascular tube formation in response to HIMF. Furthermore, HIMF and its human homolog, resistin-like molecule-β, significantly increased interleukin (IL)-6 in macrophages and lung resident cells through a mechanism dependent on HIF-1α and, at least to some extent, on nuclear factor κB.
  
  
  CONCLUSIONS
  Our results suggest that HIF-1α is a critical downstream transcription factor for HIMF-induced pulmonary vascular remodeling and PH development. Importantly, both HIMF and human resistin-like molecule-β significantly increased IL-6 in lung resident cells and increased perivascular accumulation of IL-6-expressing macrophages in the lungs of mice. These data suggest that HIMF can induce HIF-1, vascular endothelial growth factor-A, and interleukin-6, which are critical mediators of both hypoxic inflammation and PH pathophysiology.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine (R.A.J., L.W.M., E.E., A.Z., N.M.H., K.Y.-K.), the Division of Cardiology (E.T.), and Vascular Program, Institute for Cell Engineering, Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry (G.L.S.), McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Johns
authors.affiliation: Department of Anesthesiology and Critical Care Medicine (R.A.J., L.W.M., E.E., A.Z., N.M.H., K.Y.-K.), the Division of Cardiology (E.T.), and Vascular Program, Institute for Cell Engineering, Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry (G.L.S.), McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD.
authors.forename: Eiki
authors.initials: E
authors.lastname: Takimoto
authors.affiliation: Department of Anesthesiology and Critical Care Medicine (R.A.J., L.W.M., E.E., A.Z., N.M.H., K.Y.-K.), the Division of Cardiology (E.T.), and Vascular Program, Institute for Cell Engineering, Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry (G.L.S.), McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD.
authors.forename: Lucas W
authors.initials: LW
authors.lastname: Meuchel
authors.affiliation: Department of Anesthesiology and Critical Care Medicine (R.A.J., L.W.M., E.E., A.Z., N.M.H., K.Y.-K.), the Division of Cardiology (E.T.), and Vascular Program, Institute for Cell Engineering, Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry (G.L.S.), McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD.
authors.forename: Esra
authors.initials: E
authors.lastname: Elsaigh
authors.affiliation: Department of Anesthesiology and Critical Care Medicine (R.A.J., L.W.M., E.E., A.Z., N.M.H., K.Y.-K.), the Division of Cardiology (E.T.), and Vascular Program, Institute for Cell Engineering, Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry (G.L.S.), McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD.
authors.forename: Ailan
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology and Critical Care Medicine (R.A.J., L.W.M., E.E., A.Z., N.M.H., K.Y.-K.), the Division of Cardiology (E.T.), and Vascular Program, Institute for Cell Engineering, Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry (G.L.S.), McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD.
authors.forename: Nicola M
authors.initials: NM
authors.lastname: Heller
authors.affiliation: Department of Anesthesiology and Critical Care Medicine (R.A.J., L.W.M., E.E., A.Z., N.M.H., K.Y.-K.), the Division of Cardiology (E.T.), and Vascular Program, Institute for Cell Engineering, Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry (G.L.S.), McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD.
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.affiliation: Department of Anesthesiology and Critical Care Medicine (R.A.J., L.W.M., E.E., A.Z., N.M.H., K.Y.-K.), the Division of Cardiology (E.T.), and Vascular Program, Institute for Cell Engineering, Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry (G.L.S.), McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD. kkegan1@jhmi.edu.
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Yamaji-Kegan
mesh_terms: D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation; D002465:Cell Movement; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005838:Genotype; D006439:Hemodynamics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D010641:Phenotype; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D066253:Vascular Remodeling
chemical_list: C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; C486574:RETNLB protein, human; C413576:Retnla protein, mouse; D042461:Vascular Endothelial Growth Factor A; C577686:interleukin-6, mouse; C467480:vascular endothelial growth factor A, mouse; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: hypertension; hypoxia-inducible factor 1; interleukins; macrophages; pulmonary; resistin-like molecule