Glyceollins inhibit platelet-derived growth factor-mediated human arterial smooth muscle cell proliferation and migration

Platelet-derived growth factor (PDGF)-BB can induce abnormal proliferation and migration of vascular smooth muscle cells (VSMC) that are involved in the development of CVD. In our preliminary study, phytoalexin glyceollins (glyceollins I, II and III) isolated from soyabean seeds cultured with Aspergillus sojae showed strong antioxidant and anti-inflammatory activity. Since antioxidants showed beneficial effects on chronic inflammatory diseases, the purpose of the present study was to examine the effects of glyceollins on PDGF-induced proliferation and migration in human aortic smooth muscle cells (HASMC). Incubation of resting HASMC with glyceollins for 24 h significantly diminished PDGF-increased cell number and DNA synthesis in a dose-dependent manner without any cytotoxicity. In addition to blocking of the PDGF-inducible progression through the G0/G1 to the S phase of the cell cycle, glyceollins down-regulated the expression of cyclin-dependent kinase (CDK)2 and cyclin D1, and up-regulated the expression of CDK inhibitors such as p27kip1 and p53.Glyceollins also effectively inhibited Reactive Oxygen Species generation and phosphorylation of PDGF receptor-β, Phospholipase Cγ1, Akt and extracellular signal-regulated kinase 1/2 by PDGF stimulation. Furthermore, glyceollins were found to inhibit PDGF-induced dissociation of actin filaments and cell migration. Thus, the results suggest that glyceollins could become a potent therapeutic agent for regulating VSMC-associated vascular disease such as atherosclerosis and restenosis after angioplasty.