Mouse genetic evidence that tranilast reduces smooth muscle cell hyperplasia via a p21(WAF1)-dependent pathway.
OBJECTIVE
N-(3'4'-dimethoxycinnamoyl)-anthranilic acid (tranilast) is a drug that has been shown to reduce the incidence of restenosis after angioplasty in middle-scale clinical trials. Despite clinical interest in this drug, the pharmacological actions of tranilast remain relatively unexplored at a molecular level.


RESULTS
We evaluated the effects of tranilast on vascular smooth muscle cell (VSMC) proliferation in wild-type mice and in mice lacking a cyclin-dependent kinase inhibitor, p21(WAF1) (p21). Tranilast potently inhibited the proliferation of VSMC cultures derived from wild-type mice, but VSMCs derived from p21-deficient (p21-/-) mice were unaffected by this treatment. In a mouse femoral artery model of vascular injury, tranilast administration to wild-type mice led to an upregulation of p21 expression and a decrease in the number of proliferating VSMCs, as determined by immunostaining for proliferating cell nuclear antigen. In contrast, tranilast had no effect on the number of proliferating cell nuclear antigen-positive cells in the injured arteries of p21-/- mice. Administration of tranilast significantly reduced the neointimal VSMC hyperplasia in wild-type mice at 4 weeks but had no effect on lesion formation in p21-/- mice.


CONCLUSIONS
Our findings provide genetic evidence that tranilast inhibits intimal hyperplasia via a p21-dependent pathway, an activity that may contribute to its efficacy in the prophylactic treatment of postangioplasty restenosis.
Sata
Masataka
M
Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan. msata-circ@umin.ac.jp
Takahashi
Akihiro
A
Tanaka
Kimie
K
Washida
Miwa
M
Ishizaka
Nobukazu
N
Ako
Junya
J
Yoshizumi
Masao
M
Ouchi
Yasuyoshi
Y
Taniguchi
Takahiro
T
Hirata
Yasunobu
Y
Yokoyama
Mitsuhiro
M
Nagai
Ryozo
R
Walsh
Kenneth
K
D000818:Animals; D001161:Arteriosclerosis / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000187:drug effects* / Q000378:metabolism*; D006965:Hyperplasia / Q000517:prevention & control; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D010766:Phosphorylation; D012008:Recurrence; D016160:Retinoblastoma Protein / Q000378:metabolism; D015854:Up-Regulation; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016160:Retinoblastoma Protein; D062367:ortho-Aminobenzoates; C012293:tranilast