TAS-301,a new synthetic inhibitor of neointimal thickening after balloon injury, inhibits calcium-dependent signal transduction and cytoskeletal reorganization

We previously demonstrated that a recently synthesized drug, TAS-301 [3-bis (4-methoxyphenyl)methylene-2-indolinone], inhibited neointimal thickening a fter single-balloon injury to the rat com mon carotid artery by inhibiting both the migration and proliferation processes of vascular smooth muscle ce lls (VSMCs). The purpose of this current study was to elucidate the possibl e mechanism of action for its inhibition of the migration process of VSMCs. We also determined the efficacy of TAS-301 on second neointimal formation 14 days after a double-balloon injury to the rat common carotid artery. Neo intimal thickening, 14 days after second balloon injury, was reduced by the oral administration of TAS-301 in a dose-dependent manner. In in vitro ass ays using rat VSMCs, Western blot analysis showed that TAS-301 inhibited pl atelet-derived growth factor (PDGF)-induced tyrosine phosphorylation of bot h focal adhesion kinase and paxillin. Tyrosine phosphorylation of these pro teins depended on the increment of intracellular calcium concentration ([Ca 2+](i)). The PDGF-induced elevation of [Ca2+](i) and activation of Ca2+/cal modulin-dependent protein kinase II (CaM kinase II) were also inhibited by TAS-301. Additionally, TAS-301 at 10 mu mol/l reduced the extent of F-actin stress fiber depolymerization observed in response to PDGF. These results indicate that TAS-301 reduced the intimal thickening after denudation to a preexisting lesion to the same extent as it reduced that after a single-bal loon injury to the normal artery. Furthermore, the results of our in vitro experiments suggest that antimigratory mech an isms of TAS-301 that contrib ute to preventing the intimal thickening might be mediated by drug inhibiti on of Ca2+-dependent signal molecules and the following cytoskeletal depoly merization. Copright (C) 2001, KargerAG, Basel.