on May 18, 2006
Published online before print May 18, 2006, doi: 10.1161/01.ATV.0000227514.50065.2a
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Submitted on July 21, 2004
Accepted on May 3, 2006
Augmentation of Proliferation of Vascular Smooth Muscle Cells by Plasminogen Activator Inhibitor Type 1
Yabing Chen *;
From the Department of Medicine and the Cardiovascular Research Institute (Y.C., R.C.B., R.J.K., B.E.S., D.J.S.), University of Vermont, Burlington; and the Department of Pathology (Y.C.), University of Alabama at Birmingham.
* To whom correspondence should be addressed. E-mail: ybchen{at}path.uab.edu.
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.
Methods and 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-
B and activation of extracellular signal-regulated kinase (ERK) were demonstrated in SM22-PAI+-VSMCs (fold=NF-B=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-B 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-B 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.
Key words: proliferation • VSMC • plasminogen activator inhibitor type 1 • FLIP • restenosis
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