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Arterioscler Thromb Vasc Biol. 2006 Aug;26(8):1777-83. Epub 2006 May 18.

Augmentation of proliferation of vascular smooth muscle cells by plasminogen activator inhibitor type 1.

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  • 1Department of Medicine and Cardiovascular Research Institute, University of Vermont, Burlington, USA. ybchen@path.uab.edu

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.

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-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.

PMID:
16709941
[PubMed - indexed for MEDLINE]
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