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 angiotens in (ANG) II. Because chymase is synthesized mainly in mast cells, we assume d that the chymase-dependent ANG II formation could be downregulated by tra nilast. a mast cell-stabilizing antiallergic agent. We have assessed inhibi tory effects of tranilast on neointima formation after balloon injury in th e carotid artery of dogs, which share a similar ANG II-forming chymase with humans, and further explored the pathophysiological significance of vascul ar chymase, Methods and Results-Either tranilast (50 mg/kg BID) or vehicle was orally a dministered to beagles for 2 weeks before and 4 weeks after balloon injury, Four weeks after the injury, remarkable neointima was formed in the caroti d arteries of vehicle-treated dogs. Chymase mRNA levels and chymaselike act ivity 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 decre ased the carotid intima/media ratio by 63%. In vehicle-treated injured arte ries, 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 specifi cally 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.