Tranilast suppresses vascular chymase expression and neointima formation in balloon-injured dog carotid artery.
BACKGROUND
Activation of vascular chymase plays a major role in myointimal hypertrophy after vascular injury by augmenting the production of angiotensin (ANG) II. Because chymase is synthesized mainly in mast cells, we assumed that the chymase-dependent ANG II formation could be downregulated by tranilast, a mast cell-stabilizing antiallergic agent. We have assessed inhibitory effects of tranilast on neointima formation after balloon injury in the carotid artery of dogs, which share a similar ANG II-forming chymase with humans, and further explored the pathophysiological significance of vascular chymase.


RESULTS
Either tranilast (50 mg/kg BID) or vehicle was orally administered to beagles for 2 weeks before and 4 weeks after balloon injury. Four weeks after the injury, remarkable neointima was formed in the carotid arteries of vehicle-treated dogs. Chymase mRNA levels and chymaselike activity of vehicle-treated injured arteries were increased 10.2- and 4.8-fold, respectively, those of uninjured arteries. Angiotensin-converting enzyme (ACE) activity was slightly increased in the injured arteries, whereas ACE mRNA levels were not. Tranilast treatment completely prevented the increase in chymaselike activity, reduced the chymase mRNA levels by 43%, and decreased the carotid intima/media ratio by 63%. In vehicle-treated injured arteries, mast cell count in the adventitia showed a great increase, which was completely prevented by the tranilast treatment. Vascular ACE activity and mRNA levels were unaffected by tranilast.


CONCLUSIONS
Tranilast suppressed chymase gene expression, which was specifically activated in the injured arteries, and prevented neointima formation. Suppression of the chymase-dependent ANG II-forming pathway may contribute to the beneficial effects of tranilast.
Shiota
N
N
Department of Pharmacology, Osaka Medical College, Takatsuki, Japan.
Okunishi
H
H
Takai
S
S
Mikoshiba
I
I
Sakonjo
H
H
Shibata
N
N
Miyazaki
M
M
D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D002339:Carotid Arteries / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D002404:Catheterization; D053818:Chymases; D004285:Dogs; D008297:Male; D008407:Mast Cells / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D012083:Renin / Q000097:blood; D012697:Serine Endopeptidases / Q000097:blood / Q000187:drug effects* / Q000235:genetics; D062367:ortho-Aminobenzoates / Q000493:pharmacokinetics / Q000494:pharmacology*
D018926:Anti-Allergic Agents; D012333:RNA, Messenger; D062367:ortho-Aminobenzoates; D007703:Peptidyl-Dipeptidase A; D012697:Serine Endopeptidases; D053818:Chymases; D012083:Renin; C012293:tranilast