title: Therapeutic effect of magnesium lithospermate B on neointimal formation after balloon-induced vascular injury.
abstract: 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.
authors.affiliation: Brain Korea 21 Project for Medical Science, Yonsei University, Seoul, Republic of Korea.
authors.forename: Kyu Yeon
authors.initials: KY
authors.lastname: Hur
authors.forename: Hye Jun
authors.initials: HJ
authors.lastname: Seo
authors.forename: Eun Seok
authors.initials: ES
authors.lastname: Kang
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Seungjeong
authors.initials: S
authors.lastname: Song
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Kim
authors.forename: Soyeon
authors.initials: S
authors.lastname: Lim
authors.forename: Chulhee
authors.initials: C
authors.lastname: Choi
authors.forename: Ji Hoe
authors.initials: JH
authors.lastname: Heo
authors.forename: Ki Chul
authors.initials: KC
authors.lastname: Hwang
authors.forename: Chul Woo
authors.initials: CW
authors.lastname: Ahn
authors.forename: Bong Soo
authors.initials: BS
authors.lastname: Cha
authors.forename: Mankil
authors.initials: M
authors.lastname: Jung
authors.forename: Hyun Chul
authors.initials: HC
authors.lastname: Lee
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects; D015153:Blotting, Western; D020212:Carotid Artery Injuries / Q000188:drug therapy* / Q000473:pathology*; D002404:Catheterization; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D004365:Drugs, Chinese Herbal / Q000302:isolation & purification / Q000627:therapeutic use*; D004591:Electrophoresis, Polyacrylamide Gel; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D007150:Immunohistochemistry; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D018517:Plant Roots / Q000737:chemistry; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D027561:Salvia miltiorrhiza / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D000975:Antioxidants; D004365:Drugs, Chinese Herbal; D016166:Free Radical Scavengers; D010982:Platelet-Derived Growth Factor; D017382:Reactive Oxygen Species; C061091:lithospermate B