title: Ginkgolide A-gold nanoparticles inhibit vascular smooth muscle proliferation and migration in vitro and reduce neointimal hyperplasia in a mouse model.
abstract: BACKGROUND
  Neointimal formation is mediated by phenotypic changes in vascular smooth muscle cells (SMC) and is an important mediator of restenosis following arterial reconstruction. We conjugated antioxidant ginkgolide A (GA) to gold nanoparticles (GNP) to determine the effect of GA delivery on neointimal formation.
  
  
  METHODS
  GA was conjugated to 80 nm GNP in an overnight incubation. Mouse P53LMAC01 vascular SMC were treated with various doses of GA-GNP, GA alone, GNP alone, and no treatment control. Cell proliferation and migration were analyzed, and superoxide anion levels and the phosphorylation status of ERK1/2 were determined. Mice underwent ligation of the common carotid artery along with local treatment with GNP (control) or GA-GNP. The carotid artery was harvested and subjected to immunohistochemical analysis.
  
  
  RESULTS
  GA-GNP treatment significantly inhibited SMC proliferation and migration in vitro in comparison to GNP treatment alone, and the effect persisted for up to 72 h after treatment. Treatment with GA-GNP also reduced superoxide anion levels in vitro. PDGF-BB substantially induced ERK1/2 phosphorylation in GNP control cells; this PDGE-BB induced ERK1/2 phosphorylation was significantly inhibited in GA-GNP-treated cells compared with GNP only. GA-GNP significantly reduced neointimal hyperplasia after injury in mice, and proliferating cell nuclear antigen (PCNA) staining was reduced substantially in the arteries of mice treated with GA-GNP.
  
  
  CONCLUSIONS
  GA-GNP reduce vascular SMC proliferation and migration in vitro through reduced activation of ERK1/2. Local treatment with GA-GNP in areas of arterial injury reduced neointimal hyperplasia and subsequent stenosis.
authors.affiliation: Molecular Surgeon Research Center, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Weakley
authors.forename: Xinwen
authors.initials: X
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Mu
authors.forename: Jianming
authors.initials: J
authors.lastname: Lü
authors.forename: Peter H
authors.initials: PH
authors.lastname: Lin
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Yao
authors.forename: Changyi
authors.initials: C
authors.lastname: Chen
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D046934:Ginkgolides / Q000494:pharmacology*; D006046:Gold / Q000494:pharmacology*; D006965:Hyperplasia / Q000188:drug therapy; D066298:In Vitro Techniques; D007783:Lactones / Q000494:pharmacology*; D053768:Metal Nanoparticles / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000473:pathology; D058426:Neointima / Q000188:drug therapy* / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D013481:Superoxides / Q000037:antagonists & inhibitors
chemical_list: D046934:Ginkgolides; D007783:Lactones; D010982:Platelet-Derived Growth Factor; D013481:Superoxides; D006046:Gold; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C477042:ginkgolide A