PMID- 26769965
OWN - NLM
STAT- MEDLINE
DCOM- 20160809
LR  - 20220318
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 291
IP  - 10
DP  - 2016 Mar 4
TI  - Heparin Decreases in Tumor Necrosis Factor alpha (TNFalpha)-induced Endothelial Stress 
      Responses Require Transmembrane Protein 184A and Induction of Dual Specificity 
      Phosphatase 1.
PG  - 5342-54
LID - 10.1074/jbc.M115.681288 [doi]
AB  - Despite the large number of heparin and heparan sulfate binding proteins, the 
      molecular mechanism(s) by which heparin alters vascular cell physiology is not 
      well understood. Studies with vascular smooth muscle cells (VSMCs) indicate a 
      role for induction of dual specificity phosphatase 1 (DUSP1) that decreases ERK 
      activity and results in decreased cell proliferation, which depends on specific 
      heparin binding. The hypothesis that unfractionated heparin functions to decrease 
      inflammatory signal transduction in endothelial cells (ECs) through 
      heparin-induced expression of DUSP1 was tested. In addition, the expectation that 
      the heparin response includes a decrease in cytokine-induced cytoskeletal changes 
      was examined. Heparin pretreatment of ECs resulted in decreased TNFalpha-induced JNK 
      and p38 activity and downstream target phosphorylation, as identified through 
      Western blotting and immunofluorescence microscopy. Through knockdown strategies, 
      the importance of heparin-induced DUSP1 expression in these effects was 
      confirmed. Quantitative fluorescence microscopy indicated that heparin treatment 
      of ECs reduced TNFalpha-induced increases in stress fibers. Monoclonal antibodies 
      that mimic heparin-induced changes in VSMCs were employed to support the 
      hypothesis that heparin was functioning through interactions with a receptor. 
      Knockdown of transmembrane protein 184A (TMEM184A) confirmed its involvement in 
      heparin-induced signaling as seen in VSMCs. Therefore, TMEM184A functions as a 
      heparin receptor and mediates anti-inflammatory responses of ECs involving 
      decreased JNK and p38 activity.
CI  - (c) 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Farwell, Sara Lynn N
AU  - Farwell SL
AD  - From the Department of Biological Sciences, Lehigh University, Bethlehem, 
      Pennsylvania 18015.
FAU - Kanyi, Daniela
AU  - Kanyi D
AD  - From the Department of Biological Sciences, Lehigh University, Bethlehem, 
      Pennsylvania 18015, the Department of Chemistry, Lehigh University, Allentown, 
      Pennsylvania 18103.
FAU - Hamel, Marianne
AU  - Hamel M
AD  - From the Department of Biological Sciences, Lehigh University, Bethlehem, 
      Pennsylvania 18015.
FAU - Slee, Joshua B
AU  - Slee JB
AD  - From the Department of Biological Sciences, Lehigh University, Bethlehem, 
      Pennsylvania 18015, the Department of Natural Sciences, DeSales University, 
      Center Valley, Pennsylvania 18034.
FAU - Miller, Elizabeth A
AU  - Miller EA
AD  - From the Department of Biological Sciences, Lehigh University, Bethlehem, 
      Pennsylvania 18015.
FAU - Cipolle, Mark D
AU  - Cipolle MD
AD  - the Department of Surgery, Lehigh Valley Hospital Center, Allentown, Pennsylvania 
      18103, and.
FAU - Lowe-Krentz, Linda J
AU  - Lowe-Krentz LJ
AD  - From the Department of Biological Sciences, Lehigh University, Bethlehem, 
      Pennsylvania 18015, LJL0@lehigh.edu.
LA  - eng
GR  - R15 HL054269/HL/NHLBI NIH HHS/United States
GR  - HL54269/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 - 20160114
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Membrane Proteins)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Tmem184a protein, human)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (Vesicular Transport Proteins)
RN  - 9005-49-6 (Heparin)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 4)
RN  - EC 3.1.3.48 (DUSP1 protein, human)
RN  - EC 3.1.3.48 (Dual Specificity Phosphatase 1)
SB  - IM
MH  - Animals
MH  - Cattle
MH  - Cell Line
MH  - Dual Specificity Phosphatase 1/genetics/*metabolism
MH  - Endothelial Cells/drug effects/*metabolism
MH  - Endothelium, Vascular/cytology
MH  - Heparin/*pharmacology
MH  - Humans
MH  - MAP Kinase Kinase 4/metabolism
MH  - MAP Kinase Signaling System
MH  - Membrane Proteins
MH  - Muscle, Smooth, Vascular/cytology
MH  - Myocytes, Smooth Muscle/drug effects/metabolism
MH  - Rats
MH  - Receptors, Cell Surface/genetics/*metabolism
MH  - Stress Fibers/*metabolism
MH  - Tumor Necrosis Factor-alpha/*metabolism
MH  - Vesicular Transport Proteins
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
PMC - PMC4777865
OTO - NOTNLM
OT  - JNK
OT  - actin
OT  - endothelial cell
OT  - heparin-binding protein
OT  - inflammation
OT  - p38 MAPK
EDAT- 2016/01/16 06:00
MHDA- 2016/08/10 06:00
PMCR- 2017/03/04
CRDT- 2016/01/16 06:00
PHST- 2015/07/24 00:00 [received]
PHST- 2016/01/16 06:00 [entrez]
PHST- 2016/01/16 06:00 [pubmed]
PHST- 2016/08/10 06:00 [medline]
PHST- 2017/03/04 00:00 [pmc-release]
AID - S0021-9258(20)43169-2 [pii]
AID - M115.681288 [pii]
AID - 10.1074/jbc.M115.681288 [doi]
PST - ppublish
SO  - J Biol Chem. 2016 Mar 4;291(10):5342-54. doi: 10.1074/jbc.M115.681288. Epub 2016 
      Jan 14.