Anti-competence Effects of Synthetic Phthalide Derivatives on Platelet-Derived Growth Factor-Induced DNA Synthesis in Primary Cultures of Rat Aorta Smooth Muscle Cells

Abstract

The inhibitory effect of 3-butylidene-4, 5-dihydroxyphthalide (BP-42) on platelet derived growth factor (PDGF)-BB-induced DNA synthesis was investigated in synchronized smooth muscle cells (SMC) in primary culture of rat aorta. BP-42 (0.3-3μg/ml) inhibited the PDGF-BB (30 ng/ml)-stimulated [³H]thymidine incorporation of the SMC in a concentration-dependent manner. BP-42 inhibited both the competence and progression phases of [³H] thymidine incorporation induced by PDGF-BB. Using the competence assay, BP-42 (0.3-10 μg/ml) delayed PDGF-BB (30 ng/ml)-accelerated starting time of [³H] thymidine incorporation in a concentration-dependent manner, confirming that BP-42 inhibited PDGF-BB-induced competence phase of DNA synthesis of SMC. BP-42 (1-10 μg/ml) also delayed basic fibroblast growth factor (bFGF : 30 ng/ml)-accelerated starting time of [³H] thymidine incorporation. The inhibitory potency of BP-42 for the competence action of PDGF-BB was similar to that for the action of bFGF. BP-421 (3-heptylidene-4, 5-dihydroxyphthalide) and BP-422 (3-benzylidene-4, 5-dihydroxyphthalide) had 3-fold greater inhibitory potencies than BP-42 for the PDGF-BB-induced competence activity. These results demonstrated that BP-42 inhibited PDGF-BB-induced competence activity of DNA synthesis in primary cultured SMC of rat aorta via a common signal transduction mechanism with bFGF. BP-421 and BP-422 were more potent inhibitors for the competence activity, suggesting that they may become a prototype of new anti-atherosclerotic drugs.