Transcription factor decoy for activator protein-1 (AP-1) inhibits high glucose- and angiotensin II-induced type 1 plasminogen activator inhibitor (PAI-1) gene expression in cultured human vascular smooth muscle cells.
OBJECTIVE
Multiple factors, including hyperglycaemia and angiotensin II (Ang II), stimulate plasminogen activator inhibitor-1 (PAI-1) gene expression in human vascular smooth muscle cells. This study tested the hypothesis that hyperglycaemia and Ang II stimulate PAI-1 gene expression through activator protein-1 (AP-1) binding sites.


METHODS
We evaluated the role of AP-1 in PAI-1 gene expression in human vascular smooth muscle cells under high D-glucose and Ang II stimulation using a double-stranded cis-element AP-1 oligodeoxynucleotide (decoy ODN).


RESULTS
Activator protein 1 activity was stimulated by high glucose and Ang II treatment and the AP-1 decoy ODN, but not a mismatched decoy ODN, competed for AP-1 activity. The increase in PAI-1 expression by high glucose and Ang II was significantly attenuated by the AP-1 decoy ODN (p <0.05 or p < 0.01). The increase in PAI-1 expression by high glucose and Ang II action on AP-1 sites was also confirmed by promoter analysis of PAI-1. Activator protein 1 activation in response to either high glucose or co-stimulation with high glucose and Ang II was inhibited completely by calphostin C (a PKC inhibitor) and partially by genistein (a protein tyrosine kinase inhibitor).


CONCLUSIONS
This study shows that high glucose and Ang II stimulate PAI-1 expression through AP-1 binding sites. Signal transduction after AP-1 activation by both high glucose and Ang II largely depends on PKC activation. These data indicate an important role for AP-1 in PAI-1 expression.
Ahn
J D
JD
Institute for Medical Science, Keimyung University School of Medicine, Taegu, Korea.
Morishita
R
R
Kaneda
Y
Y
Lee
K U
KU
Park
J Y
JY
Jeon
Y J
YJ
Song
H S
HS
Lee
I K
IK
D000804:Angiotensin II / Q000494:pharmacology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D019833:Genistein / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D009281:Naphthalenes / Q000494:pharmacology; D009841:Oligonucleotides / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D018808:Transcription Factor AP-1 / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology
D004791:Enzyme Inhibitors; D009281:Naphthalenes; D009841:Oligonucleotides; D017395:Plasminogen Activator Inhibitor 1; D018808:Transcription Factor AP-1; D000804:Angiotensin II; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; C058819:calphostin C; D005947:Glucose