Vascular smooth muscle cell (VSMC) proliferation and migration in response to
platelet-derived growth factor (PDGF) play an important role in the development of
atherosclerosis and restenosis. Recent evidence indicates that PDGF increases intracellular levels of
reactive oxygen species in VSMCs and that both PDGF-induced VSMC proliferation and migration are
reactive oxygen species-dependent. Danshen is a representative
oriental medicine used for the treatment of
vascular disease. Previously, we reported that
magnesium lithospermate B, an active component of Danshen, is a potent
antioxidant. Thus we investigated the therapeutic potential of
magnesium lithospermate B in neointimal formation after
carotid artery injury in rats along with its effects on the PDGF signaling pathway for stimulating VSMC proliferation and migration in vitro. PDGF is dimeric
glycoprotein composed of two A or two B chains. In this study, we used
PDGF-BB, which is one of the
isoforms of PDGF (i.e.,
PDGF-AA,
PDGF-BB, and
PDGF-AB). Our results demonstrated that
magnesium lithospermate B directly scavenged
reactive oxygen species in a
xanthine/
xanthine oxidase system and reduced
PDGF-BB-induced intracellular
reactive oxygen species generation in VSMCs. In a rat carotid artery balloon injury model,
magnesium lithospermate B treatment (10 mg/kg/day, i.p) showed a significant effect on the prevention of neointimal formation compared with vehicle treatment. In cultured VSMCs,
magnesium lithospermate B significantly attenuated
PDGF-BB-induced cell proliferation and migration as measured by 3-[4,5-dimethyl-2-thiazolyl]-2,5-
diphenyl-2-tetrazolium
bromide (MTT) assay and transwell migration assays, respectively. Further,
magnesium lithospermate B inhibited
PDGF-BB-induced phosphorylation of phospatidylinositol 3-kinase (PI3K)/Akt and
mitogen-activated protein kinase (MAPK)/
extracellular signal-regulated kinase (ERK) pathways by scavenging
reactive oxygen species. Together, these data indicated that
magnesium lithospermate B, a potent
reactive oxygen species scavenger, prevented both injury-induced neointimal formation in vivo and
PDGF-BB-induced VSMC proliferation and migration in vitro, suggesting that
magnesium lithospermate B may be a promising agent to prevent
atherosclerosis and restenosis following angioplasty.