Inhibitory Effect of TAS-301, a New Synthesized Constrictive Remodeling Regulator, on Renarrowing after Balloon Overstretch Injury of Porcine Coronary Artery

Abstract

The purpose of this study was to determine the efficacy and the possible mechanism of action of a recently synthesized drug, TAS-301 [3-bis(4-methoxyphenyl)methylene-2-indolinone], on stenosis after balloon overstretch injury of porcine arteries. We measured the diameter of vessels by angiography and conducted histological analysis. The oral administration of TAS-301 kept dilated the angiographic luminal diameter of injured segment 4 weeks after overstretch injury and reduced calculated stenosis ratio in a dose-dependent manner, significantly reducing it at doses of 30 and 100 mg/kg. Histopathological analysis showed that TAS-301 significantly reduced the adventitial area at doses of 30 and 100 mg/kg with moderate reduction of the neointimal area, resulting in the larger residual lumen. In an in vitro assay, TAS-301 dose dependently inhibited the proliferation of adventitial fibroblasts stimulated by basic fibroblast growth factor or transforming growth factor-β₁. In addition, the drug reduced adventitial fibroblast-mediated three-dimensional collagen gel contraction. These findings indicate that TAS-301, the first compound developed for targeting the constrictive remodeling, showed a high inhibitory potency on coronary artery stenosis of micropigs after injury, mainly due to inhibition of adventitial fibroblast proliferation and of the contractile ability of myofibroblasts. Our results suggest the strong possibility that TAS-301 may be efficacious for prevention of restenosis after angioplasty and the need to examine the therapeutic usefulness of this drug in clinical trials.