Therapeutic effect of magnesium lithospermate B on neointimal formation after balloon-induced vascular injury.
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.
Hur
Kyu Yeon
KY
Brain Korea 21 Project for Medical Science, Yonsei University, Seoul, Republic of Korea.
Seo
Hye Jun
HJ
Kang
Eun Seok
ES
Kim
Soo Hyun
SH
Song
Seungjeong
S
Kim
Eun Hee
EH
Lim
Soyeon
S
Choi
Chulhee
C
Heo
Ji Hoe
JH
Hwang
Ki Chul
KC
Ahn
Chul Woo
CW
Cha
Bong Soo
BS
Jung
Mankil
M
Lee
Hyun Chul
HC
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
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