PMID- 24098801
OWN - NLM
STAT- MEDLINE
DCOM- 20140616
LR  - 20220224
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 9
DP  - 2013
TI  - Progranulin protects vascular endothelium against atherosclerotic inflammatory 
      reaction via Akt/eNOS and nuclear factor-kappaB pathways.
PG  - e76679
LID - 10.1371/journal.pone.0076679 [doi]
LID - e76679
AB  - OBJECTIVE: Atherosclerosis is considered a chronic inflammatory disease, 
      initiated by activation and dysfunction of the endothelium. Recently, progranulin 
      has been regarded as an important modulator of inflammatory processes; however, 
      the role for prgranulin in regulating inflammation in vascular endothelial cells 
      has not been described. METHOD AND RESULTS: Signaling pathways mediated by 
      progranulin were analyzed in human umbilical vein endothelial cells (HUVECs) 
      treated with progranulin. Progranulin significantly induced Akt and endothelial 
      nitric oxide synthase (eNOS) phosphorylation in HUVECs, an effect that was 
      blocked with Akt inhibitor. Furthermore, nitric oxide (NO) level, the end product 
      of Akt/eNOS pathway, was significantly upregulated after progranulin treatment. 
      Next, we showed that progranulin efficiently inhibited lipopolysaccharide 
      (LPS)-mediated pro-inflammatory signaling. LPS-induced phosphorylation of IkappaB and 
      nuclear factor-kappaB (NF-kappaB) levels decreased after progranulin treatment. Also, 
      progranulin blocked translocation of NF-kappaB from the cytosol to the nucleus. In 
      addition, progranulin significantly reduced the expression of vascular cell 
      adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) by 
      inhibiting binding of NF- kappaB to their promoter regions and blocked attachment of 
      monocytes to HUVECs. Progranulin also significantly reduced the expression of 
      tumor necrosis factor receptor-alpha (TNF-alpha) and monocyte chemo-attractant protein-1 
      (MCP-1), the crucial inflammatory molecules known to aggravate atherosclerosis. 
      CONCLUSION: Progranulin efficiently inhibited LPS-mediated pro-inflammatory 
      signaling in endothelial cells through activation of the Akt/eNOS pathway and 
      attenuation of the NF-kappaB pathway, suggesting its protective roles in vascular 
      endothelium against inflammatory reaction underlying atherosclerosis.
FAU - Hwang, Hwan-Jin
AU  - Hwang HJ
AD  - Division of Endocrinology and Metabolism, Department of Internal Medicine, 
      College of Medicine, Korea University, Seoul, Korea.
FAU - Jung, Tae Woo
AU  - Jung TW
FAU - Hong, Ho Cheol
AU  - Hong HC
FAU - Choi, Hae Yoon
AU  - Choi HY
FAU - Seo, Ji-A
AU  - Seo JA
FAU - Kim, Sin Gon
AU  - Kim SG
FAU - Kim, Nan Hee
AU  - Kim NH
FAU - Choi, Kyung Mook
AU  - Choi KM
FAU - Choi, Dong Seop
AU  - Choi DS
FAU - Baik, Sei Hyun
AU  - Baik SH
FAU - Yoo, Hye Jin
AU  - Yoo HJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130930
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (CCL2 protein, human)
RN  - 0 (Chemokine CCL2)
RN  - 0 (DNA Primers)
RN  - 0 (GRN protein, human)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (NF-kappa B)
RN  - 0 (Progranulins)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (Vascular Cell Adhesion Molecule-1)
RN  - 126547-89-5 (Intercellular Adhesion Molecule-1)
RN  - EC 1.14.13.39 (NOS3 protein, human)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type III)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Atherosclerosis/*physiopathology
MH  - Blotting, Western
MH  - Chemokine CCL2/metabolism
MH  - Chromatin Immunoprecipitation
MH  - DNA Primers/genetics
MH  - Endothelium, Vascular/*metabolism/pathology
MH  - Gene Expression Regulation/genetics/*physiology
MH  - Human Umbilical Vein Endothelial Cells
MH  - Humans
MH  - Inflammation Mediators/*metabolism
MH  - Intercellular Adhesion Molecule-1/metabolism
MH  - Intercellular Signaling Peptides and Proteins/*metabolism
MH  - Microscopy, Fluorescence
MH  - NF-kappa B/metabolism
MH  - Nitric Oxide Synthase Type III/metabolism
MH  - Progranulins
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Real-Time Polymerase Chain Reaction
MH  - Signal Transduction/*physiology
MH  - Tumor Necrosis Factor-alpha/metabolism
MH  - Vascular Cell Adhesion Molecule-1/metabolism
PMC - PMC3786912
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2013/10/08 06:00
MHDA- 2014/06/17 06:00
PMCR- 2013/09/30
CRDT- 2013/10/08 06:00
PHST- 2013/07/09 00:00 [received]
PHST- 2013/08/25 00:00 [accepted]
PHST- 2013/10/08 06:00 [entrez]
PHST- 2013/10/08 06:00 [pubmed]
PHST- 2014/06/17 06:00 [medline]
PHST- 2013/09/30 00:00 [pmc-release]
AID - PONE-D-13-28883 [pii]
AID - 10.1371/journal.pone.0076679 [doi]
PST - epublish
SO  - PLoS One. 2013 Sep 30;8(9):e76679. doi: 10.1371/journal.pone.0076679. eCollection 
      2013.