Augmentation of proliferation of vascular smooth muscle cells by plasminogen activator inhibitor type 1.
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.
Chen
Yabing
Y
Department of Medicine and Cardiovascular Research Institute, University of Vermont, Burlington, USA. ybchen@path.uab.edu
Budd
Ralph C
RC
Kelm
Robert J
RJ
Sobel
Burton E
BE
Schneider
David J
DJ
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
D016328:NF-kappa B; D017395:Plasminogen Activator Inhibitor 1; D048049:Extracellular Signal-Regulated MAP Kinases; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020169:Caspases