PMID- 26586659
OWN - NLM
STAT- MEDLINE
DCOM- 20160502
LR  - 20181113
IS  - 1524-4636 (Electronic)
IS  - 1079-5642 (Print)
IS  - 1079-5642 (Linking)
VI  - 36
IP  - 1
DP  - 2016 Jan
TI  - Hypoxia-Inducible Factor 1alpha Is a Critical Downstream Mediator for Hypoxia-Induced 
      Mitogenic Factor (FIZZ1/RELMalpha)-Induced Pulmonary Hypertension.
PG  - 134-44
LID - 10.1161/ATVBAHA.115.306710 [doi]
AB  - 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-beta) 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. APPROACH AND 
      RESULTS: In this study, we compared the degree of HIMF-induced pulmonary vascular 
      remodeling and PH development in wild-type (HIF-1alpha(+/+)) and HIF-1alpha heterozygous 
      null (HIF-1alpha(+/-)) mice. HIMF-induced PH was significantly diminished in 
      HIF-1alpha(+/-) mice and was accompanied by a dysregulated vascular endothelial 
      growth factor-A-vascular endothelial growth factor receptor 2 pathway. HIF-1alpha 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-beta, significantly increased interleukin (IL)-6 in macrophages and lung 
      resident cells through a mechanism dependent on HIF-1alpha and, at least to some 
      extent, on nuclear factor kappaB. CONCLUSIONS: Our results suggest that HIF-1alpha is a 
      critical downstream transcription factor for HIMF-induced pulmonary vascular 
      remodeling and PH development. Importantly, both HIMF and human resistin-like 
      molecule-beta 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.
CI  - (c) 2015 American Heart Association, Inc.
FAU - Johns, Roger A
AU  - Johns RA
AD  - 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.
FAU - Takimoto, Eiki
AU  - Takimoto E
AD  - 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.
FAU - Meuchel, Lucas W
AU  - Meuchel LW
AD  - 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.
FAU - Elsaigh, Esra
AU  - Elsaigh E
AD  - 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.
FAU - Zhang, Ailan
AU  - Zhang A
AD  - 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.
FAU - Heller, Nicola M
AU  - Heller NM
AD  - 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.
FAU - Semenza, Gregg L
AU  - Semenza GL
AD  - 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.
FAU - Yamaji-Kegan, Kazuyo
AU  - Yamaji-Kegan K
AD  - 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.
LA  - eng
GR  - UL1 TR001079/TR/NCATS NIH HHS/United States
GR  - S10OD016374/OD/NIH HHS/United States
GR  - P50 HL107182/HL/NHLBI NIH HHS/United States
GR  - UH2 HL123827/HL/NHLBI NIH HHS/United States
GR  - S10 OD016374/OD/NIH HHS/United States
GR  - P50HL107182/HL/NHLBI NIH HHS/United States
GR  - 5UH2HL123827-02/HL/NHLBI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20151119
PL  - United States
TA  - Arterioscler Thromb Vasc Biol
JT  - Arteriosclerosis, thrombosis, and vascular biology
JID - 9505803
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Interleukin-6)
RN  - 0 (RETNLB protein, human)
RN  - 0 (Retnla protein, mouse)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (interleukin-6, mouse)
RN  - 0 (vascular endothelial growth factor A, mouse)
RN  - EC 2.7.10.1 (Kdr protein, mouse)
RN  - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2)
SB  - IM
CIN - Arterioscler Thromb Vasc Biol. 2019 Dec;39(12):2451-2453. PMID: 31770028
MH  - Animals
MH  - Apoptosis
MH  - Bone Marrow Transplantation
MH  - Cell Movement
MH  - Cells, Cultured
MH  - Disease Models, Animal
MH  - Epithelial Cells/metabolism/pathology
MH  - Female
MH  - Fibroblasts/metabolism
MH  - Genotype
MH  - Hemodynamics
MH  - Humans
MH  - Hypertension, Pulmonary/chemically 
      induced/genetics/*metabolism/physiopathology/prevention & control
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/deficiency/genetics/*metabolism
MH  - In Vitro Techniques
MH  - Inflammation Mediators/metabolism
MH  - *Intercellular Signaling Peptides and Proteins/metabolism
MH  - Interleukin-6/metabolism
MH  - Macrophages/*metabolism/pathology
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Organ Culture Techniques
MH  - Phenotype
MH  - Pulmonary Artery/*metabolism/pathology/physiopathology
MH  - Signal Transduction
MH  - Vascular Endothelial Growth Factor A/metabolism
MH  - Vascular Endothelial Growth Factor Receptor-2/metabolism
MH  - *Vascular Remodeling
PMC - PMC5518796
MID - NIHMS737618
OTO - NOTNLM
OT  - hypertension
OT  - hypoxia-inducible factor 1
OT  - interleukins
OT  - macrophages
OT  - pulmonary
OT  - resistin-like molecule
EDAT- 2015/11/21 06:00
MHDA- 2016/05/03 06:00
PMCR- 2017/07/20
CRDT- 2015/11/21 06:00
PHST- 2014/12/12 00:00 [received]
PHST- 2015/11/05 00:00 [accepted]
PHST- 2015/11/21 06:00 [entrez]
PHST- 2015/11/21 06:00 [pubmed]
PHST- 2016/05/03 06:00 [medline]
PHST- 2017/07/20 00:00 [pmc-release]
AID - ATVBAHA.115.306710 [pii]
AID - 10.1161/ATVBAHA.115.306710 [doi]
PST - ppublish
SO  - Arterioscler Thromb Vasc Biol. 2016 Jan;36(1):134-44. doi: 
      10.1161/ATVBAHA.115.306710. Epub 2015 Nov 19.