Open AccessTAS-301 Blocks Receptor-Operated Calcium Influx and Inhibits Rat Vascular Smooth Muscle Cell Proliferation Induced by Basic Fibroblast Growth Factor and Platelet-Derived Growth Factor
Author(s) -
Eiji Sasaki,
Yoshihisa Nozawa,
Kazuhisa Miyoshi,
Atsuhiro Kanda,
Yasundo Yamasaki,
Hidekazu Miyake,
Naosuke Matsuura
Publication year - 2000
Publication title -
japanese journal of pharmacology/japanese journal of pharmacology
Language(s) - English
Resource type - Journals
eISSN - 1347-3506
pISSN - 0021-5198
DOI - 10.1254/jjp.84.252
Subject(s) - platelet derived growth factor receptor , protein kinase c , vascular smooth muscle , platelet derived growth factor , growth factor , activator (genetics) , microbiology and biotechnology , signal transduction , cell growth , basic fibroblast growth factor , biology , phorbol , medicine , endocrinology , intracellular , calcium in biology , receptor , chemistry , biochemistry , smooth muscle
The purpose of this study was to determine the effect of a recently synthesized drug, TAS-301 [3-bis(4-methoxyphenyl)methylene-2-indolinone], on vascular smooth muscle cell (VSMC) proliferation and the intracellular signal transduction pathways involved in VSMC proliferation. In an in vitro assay, TAS-301 inhibited the proliferation of rat VSMCs stimulated by platelet-derived growth factor (PDGF)-BB, basic fibroblast growth factor, or 2% fetal bovine serum in a concentration-dependent manner. TAS-301 dose-dependently inhibited the PDGF-induced Ca2+ influx; the concentration for the inhibition of Ca2+ influx was nearly identical to that for inhibition of VSMC proliferation. The Ca2+ influx induced by PDGF was also attenuated by NiCl2 but not by nifedipine, suggesting that PDGF-induced Ca2+ influx would be mediated by some non-voltage-dependent mechanisms. Furthermore, TAS-301 inhibited PDGF-induced activation of protein kinase C (PKC) and the phorbol 12-myristate 13-acetate-mediated induction of activator protein 1 (AP-1) in a concentration-dependent manner. These findings indicate that TAS-301 inhibited the proliferation of VSMCs by blocking voltage-independent Ca2+ influx and downstream signals such as the Ca2+/PKC signaling pathway, leading to AP-1 induction.