title: Augmentation of proliferation of vascular smooth muscle cells by plasminogen activator inhibitor type 1.
abstract: OBJECTIVE
  Proliferation of vascular smooth muscle cells (VSMCs) contributes to restenosis after coronary intervention. We have shown previously that increased expression of plasminogen activator inhibitor type 1 (PAI-1) limits VSMC apoptosis. Because apoptosis and proliferation appear to be linked, we sought to determine whether increased PAI-1 would affect VSMC proliferation.
  
  
  RESULTS
  VSMCs were explanted from control and transgenic mice (SM22-PAI+) in which VSMC expression of PAI-1 was increased. Increased growth of SM22-PAI+-VSMCs (2.3+/-0.4-fold) reflected, at least partially, increased proliferation. Greater expression of FLICE-like inhibitory protein (FLIP; 2.7-fold) and its cleaved active form were seen in SM22-PAI+-VSMCs. The balance between caspase-8 and FLIP favored proliferation in SM22-PAI+-VSMCs. Increased expression of NF-kappaB and activation of extracellular signal-regulated kinase (ERK) were demonstrated in SM22-PAI+-VSMCs (fold=NF-kappaB=2.2+/-0.1, fold=phosphorylated-ERK=1.6+/-0.1). Results were confirmed when expression of PAI-1 was increased by transfection. Inhibition of NF-kappaB and ERK attenuated proliferation in SM22-PAI+-VSMCs. Increased expression of PAI-1 promoted proliferation when VSMCs were exposed to tumor necrosis factor (TNF).
  
  
  CONCLUSIONS
  Increased expression of PAI-1 is associated with greater activity of FLIP that promotes VSMC proliferation through NF-kappaB and ERK. Thus, when vascular wall expression of PAI-1 is increased, restenosis after coronary intervention is likely to be potentiated by greater proliferation of VSMC and resistance to apoptosis.
authors.affiliation: Department of Medicine and Cardiovascular Research Institute, University of Vermont, Burlington, USA. ybchen@path.uab.edu
authors.forename: Yabing
authors.initials: Y
authors.lastname: Chen
authors.forename: Ralph C
authors.initials: RC
authors.lastname: Budd
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kelm
authors.forename: Burton E
authors.initials: BE
authors.lastname: Sobel
authors.forename: David J
authors.initials: DJ
authors.lastname: Schneider
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000166:cytology* / Q000378:metabolism; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000494:pharmacology*; D014162:Transfection
chemical_list: D016328:NF-kappa B; D017395:Plasminogen Activator Inhibitor 1; D048049:Extracellular Signal-Regulated MAP Kinases; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020169:Caspases