Retinoids induce the PAI-1 gene expression through tyrosine kinase-dependent pathways in vascular smooth muscle cells.
Retinoids exert their pleiotropic effects on several pathophysiologic processes, including neointima formation after experimental vascular injury. Plasminogen activator inhibitor-1 (PAI-1) has been proposed to play an inhibitory role in arterial neointima formation after injury. We examined whether retinoids regulate PAI-1 expression in cultured vascular smooth muscle cells (SMCs). Northern blot analysis showed that all-trans retinoic acid (atRA) and 9-cis retinoic acid (9cRA) increased PAI-1 mRNA levels in a dose-dependent manner. These responses were completely inhibited by tyrosine kinase inhibitors. The half-life of PAI-1 was not affected by atRA, suggesting that induction of PAI-1 mRNA was mainly regulated at the transcriptional levels. Stable and transient transfection assays of the human PAI-1 promoter-luciferase constructs indicate that DNA sequence responsive to either ligand-stimulated or overexpressed retinoic acid receptor-alpha expression vector lies downstream of -363 relative to the transcription start site, where no putative retinoic acid response element is found. These results indicate that atRA and 9cRA increase PAI-1 gene transcription through pathways involving tyrosine kinases in SMCs. Because PAI-1 inhibits the production of fibrinolytic protein plasmin that facilitates SMC migration, induction of the PAI-1 gene expression by atRA may at least partly account for the role of atRA as an important inhibitor of neointima formation.
Watanabe
Atai
A
Second Department of Internal Medicine, Gunma University School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511, Japan.
Kanai
Hiroyoshi
H
Arai
Masashi
M
Sekiguchi
Kenichi
K
Uchiyama
Tsuyoshi
T
Nagai
Ryozo
R
Kurabayashi
Masahiko
M
D000077556:Alitretinoin; D000818:Animals; D015152:Blotting, Northern; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000032:analysis; D011817:Rabbits; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*; D017539:Tunica Intima / Q000187:drug effects
D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D000077556:Alitretinoin; D014212:Tretinoin; D011505:Protein-Tyrosine Kinases