PMID- 25036043
OWN - NLM
STAT- MEDLINE
DCOM- 20151130
LR  - 20240322
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 7
DP  - 2014
TI  - The role of Iex-1 in the pathogenesis of venous neointimal hyperplasia associated 
      with hemodialysis arteriovenous fistula.
PG  - e102542
LID - 10.1371/journal.pone.0102542 [doi]
LID - e102542
AB  - Arteriovenous fistulas (AVFs) used for hemodialysis fail because of venous 
      neointimal hyperplasia (VNH). There are 1,500,000 patients that have end stage 
      renal disease worldwide and the majority requires hemodialysis. In the present 
      study, the role of the intermediate early response gene X-1 (IEX-1), also known 
      as IER-3 in the pathogenesis of VNH was evaluated. In human samples removed from 
      failed AVF, there was a significant increase in IEX-1 expression localized to the 
      adventitia. In Iex-1-/- mice and wild type (WT) controls, chronic kidney disease 
      was induced and an AVF placed 28 days later by connecting the carotid artery to 
      jugular vein. The outflow vein was removed three days following the creation of 
      the AVF and gene expression analysis demonstrated a significant decrease in 
      vascular endothelial growth factor-A (Vegf-A) and monocyte chemoattractant 
      protein-1 (Mcp-1) gene expression in Iex-1-/- mice when compared to WT mice 
      (P<0.05). At 28 days after AVF placement, histomorphometric and 
      immune-histochemical analyses of the outflow vein demonstrated a significant 
      decrease in neointimal hyperplasia with an increase in average lumen vessel area 
      associated with a decrease in fibroblast, myofibroblast, and Ly6C staining. There 
      was a decrease in proliferation (Ki-67) and an increase in the TUNEL staining in 
      Iex-1 KO mice compared to WT. In addition, there was a decrease in Vegf-A, Mcp-1, 
      and matrix metalloproteiniase-9 (Mmp-9) staining. Iex-1 expression was reduced in 
      vivo and in vitro using nanoparticles coated with calcitriol, an inhibitor of 
      Iex-1 that demonstrated that Iex-1 reduction results in decrease in Vegf-A. In 
      aggregate, these results indicate that the absence of IEX-1 gene results in 
      reduced VNH accompanied with a decrease in proliferation, reduced fibroblast, 
      myofibroblast, and Ly6C staining accompanied with increased apoptosis mediated 
      through a reduction in Vegf-A/Mcp-1 axis and Mmp-9. Adventitial delivery of 
      nanoparticles coated with calcitriol reduced Iex-1 and VNH.
FAU - Brahmbhatt, Akshaar
AU  - Brahmbhatt A
AD  - Vascular and Interventional Radiology Translational Laboratory, Department of 
      Radiology, University of Cincinnati, Cincinnati, Ohio, United States of America.
FAU - NievesTorres, Evelyn
AU  - NievesTorres E
AD  - Vascular and Interventional Radiology Translational Laboratory, Department of 
      Radiology, University of Cincinnati, Cincinnati, Ohio, United States of America.
FAU - Yang, Binxia
AU  - Yang B
AD  - Vascular and Interventional Radiology Translational Laboratory, Department of 
      Radiology, University of Cincinnati, Cincinnati, Ohio, United States of America.
FAU - Edwards, William D
AU  - Edwards WD
AD  - Department of Lab Medicine and Pathology, University of Cincinnati, Cincinnati, 
      Ohio, United States of America.
FAU - Roy Chaudhury, Prabir
AU  - Roy Chaudhury P
AD  - Division of Nephrology and Hypertension, Department of Medicine, University of 
      Cincinnati, Cincinnati, Ohio, United States of America.
FAU - Lee, Min Kyun
AU  - Lee MK
AD  - Department of Chemical & Biomolecular Engineering, University of Illinois at 
      Urbana-Champaign, Champaign, Illinois, United States of America.
FAU - Kong, Hyunjoon
AU  - Kong H
AD  - Department of Chemical & Biomolecular Engineering, University of Illinois at 
      Urbana-Champaign, Champaign, Illinois, United States of America.
FAU - Mukhopadhyay, Debabrata
AU  - Mukhopadhyay D
AD  - Department of Biochemistry and Molecular Biology, Department of Medicine, Mayo 
      Clinic, Rochester, Minnesota, United States of America.
FAU - Kumar, Rajiv
AU  - Kumar R
AD  - Department of Biochemistry and Molecular Biology, Department of Medicine, Mayo 
      Clinic, Rochester, Minnesota, United States of America; Division of Nephrology 
      and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota, 
      United States of America.
FAU - Misra, Sanjay
AU  - Misra S
AD  - Vascular and Interventional Radiology Translational Laboratory, Department of 
      Radiology, University of Cincinnati, Cincinnati, Ohio, United States of America; 
      Department of Biochemistry and Molecular Biology, Department of Medicine, Mayo 
      Clinic, Rochester, Minnesota, United States of America.
LA  - eng
GR  - R01 HL098967/HL/NHLBI NIH HHS/United States
GR  - R01 HL109192/HL/NHLBI NIH HHS/United States
GR  - HHMI/Howard Hughes Medical Institute/United States
GR  - R01HL098967/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140718
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Hydrogels)
RN  - 0 (IER3 protein, human)
RN  - 0 (IEX-1 protein, mouse)
RN  - 0 (Immediate-Early Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (vascular endothelial growth factor A, mouse)
RN  - 1SIA8062RS (Polylactic Acid-Polyglycolic Acid Copolymer)
RN  - 26009-03-0 (Polyglycolic Acid)
RN  - 33X04XA5AT (Lactic Acid)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
RN  - FXC9231JVH (Calcitriol)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Apoptosis Regulatory Proteins/analysis/*physiology
MH  - Arteriovenous Shunt, Surgical/*adverse effects
MH  - Calcitriol/administration & dosage/pharmacology/therapeutic use
MH  - Chemokine CCL2/biosynthesis/genetics
MH  - Fibroblasts/pathology
MH  - Humans
MH  - Hydrogels
MH  - Hyperplasia
MH  - Immediate-Early Proteins/*deficiency/physiology
MH  - Kidney Failure, Chronic/therapy
MH  - Lactic Acid
MH  - Male
MH  - Matrix Metalloproteinase 9/biosynthesis/genetics
MH  - Membrane Proteins/analysis/*physiology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Myofibroblasts/pathology
MH  - Nanoparticles
MH  - Polyglycolic Acid
MH  - Polylactic Acid-Polyglycolic Acid Copolymer
MH  - *Renal Dialysis
MH  - Tunica Intima/metabolism/*pathology
MH  - Vascular Endothelial Growth Factor A/biosynthesis/genetics
MH  - Veins/*pathology
PMC - PMC4103828
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/07/19 06:00
MHDA- 2015/12/15 06:00
PMCR- 2014/07/18
CRDT- 2014/07/19 06:00
PHST- 2014/03/28 00:00 [received]
PHST- 2014/06/19 00:00 [accepted]
PHST- 2014/07/19 06:00 [entrez]
PHST- 2014/07/19 06:00 [pubmed]
PHST- 2015/12/15 06:00 [medline]
PHST- 2014/07/18 00:00 [pmc-release]
AID - PONE-D-14-14020 [pii]
AID - 10.1371/journal.pone.0102542 [doi]
PST - epublish
SO  - PLoS One. 2014 Jul 18;9(7):e102542. doi: 10.1371/journal.pone.0102542. 
      eCollection 2014.