PMID- 26379245
OWN - NLM
STAT- MEDLINE
DCOM- 20160524
LR  - 20201215
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 10
IP  - 9
DP  - 2015
TI  - Statins Increase Plasminogen Activator Inhibitor Type 1 Gene Transcription 
      through a Pregnane X Receptor Regulated Element.
PG  - e0138097
LID - 10.1371/journal.pone.0138097 [doi]
LID - e0138097
AB  - Plasminogen activator inhibitor type 1 (PAI-1) is a multifunctional protein that 
      has important roles in inflammation and wound healing. Its aberrant regulation 
      may contribute to many disease processes such as heart disease. The PAI-1 
      promoter is responsive to multiple inputs including cytokines, growth factors, 
      steroids and oxidative stress. The statin drugs, atorvastatin, mevastatin and 
      rosuvastatin, increased basal and stimulated expression of the PAI-1 promoter 
      3-fold. A statin-responsive, nuclear hormone response element was previously 
      identified in the PAI-1 promoter, but it was incompletely characterized. We 
      characterized this direct repeat (DR) of AGGTCA with a 3-nucleotide spacer at 
      -269/-255 using deletion and directed mutagenesis. Deletion or mutation of this 
      element increased basal transcription from the promoter suggesting that it 
      repressed PAI-1 transcription in the unliganded state. The half-site spacing and 
      the ligand specificity suggested that this might be a pregnane X receptor (PXR) 
      responsive element. Computational molecular docking showed that atorvastatin, 
      mevastatin and rosuvastatin were structurally compatible with the PXR 
      ligand-binding pocket in its agonist conformation. Experiments with Gal4 DNA 
      binding domain fusion proteins showed that Gal4-PXR was activated by statins 
      while other DR + 3 binding nuclear receptor fusions were not. Overexpression of 
      PXR further enhanced PAI-1 transcription in response to statins. Finally, ChIP 
      experiments using Halo-tagged PXR and RXR demonstrated that both components of 
      the PXR-RXR heterodimer bound to this region of the PAI-1 promoter.
FAU - Stanley, Frederick M
AU  - Stanley FM
AD  - Department of Biochemistry and Molecular Pharmacology, New York University School 
      of Medicine, New York, New York, United States of America; Laura and Isaac 
      Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York, United 
      States of America.
FAU - Linder, Kathryn M
AU  - Linder KM
AD  - Department of Biochemistry and Molecular Pharmacology, New York University School 
      of Medicine, New York, New York, United States of America.
FAU - Cardozo, Timothy J
AU  - Cardozo TJ
AD  - Department of Biochemistry and Molecular Pharmacology, New York University School 
      of Medicine, New York, New York, United States of America; Laura and Isaac 
      Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York, United 
      States of America.
LA  - eng
GR  - DP2 OD004631/OD/NIH HHS/United States
GR  - R21 DK067540/DK/NIDDK NIH HHS/United States
GR  - DK067540/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20150917
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
RN  - 0 (Plasminogen Activator Inhibitor 1)
RN  - 0 (Pregnane X Receptor)
RN  - 0 (Receptors, Steroid)
RN  - 0 (Retinoid X Receptors)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Gene Expression Regulation/*drug effects
MH  - Humans
MH  - Hydroxymethylglutaryl-CoA Reductase Inhibitors/metabolism/*pharmacology
MH  - Mice
MH  - Plasminogen Activator Inhibitor 1/*genetics
MH  - Pregnane X Receptor
MH  - Promoter Regions, Genetic
MH  - Protein Binding
MH  - Receptors, Steroid/metabolism/*physiology
MH  - Retinoid X Receptors/metabolism
MH  - Transcription, Genetic/*drug effects
PMC - PMC4574702
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2015/09/18 06:00
MHDA- 2016/05/25 06:00
PMCR- 2015/09/17
CRDT- 2015/09/18 06:00
PHST- 2015/05/27 00:00 [received]
PHST- 2015/08/25 00:00 [accepted]
PHST- 2015/09/18 06:00 [entrez]
PHST- 2015/09/18 06:00 [pubmed]
PHST- 2016/05/25 06:00 [medline]
PHST- 2015/09/17 00:00 [pmc-release]
AID - PONE-D-15-23070 [pii]
AID - 10.1371/journal.pone.0138097 [doi]
PST - epublish
SO  - PLoS One. 2015 Sep 17;10(9):e0138097. doi: 10.1371/journal.pone.0138097. 
      eCollection 2015.