Plasminogen activator inhibitor-1 impairs plasminogen activationmediated vascular smooth muscle cell apoptosis
- 1 January 2006
- journal article
- Published by Georg Thieme Verlag KG in Thrombosis and Haemostasis
- Vol. 96 (11), 665-670
- https://doi.org/10.1160/th06-06-0321
Abstract
The role of plasminogen activator inhibitor-1 (PAI-1) in vascular smooth muscle cell (VSMC) apoptosis mediated by plasminogen activation was studied with the use of aorticVSMC derived from mice with deficiency of PAI-1 (PAI-1-/-), tissue-type (t-PA-/-) or urokinase-type (u-PA-/-) plasminogen activator or from wildtype (WT) mice with corresponding genetic background. Plasminogen incubated with confluentVSMC was activated ina concentration-dependent and saturable manner for all four cell types, with maximal activation rates that were comparable for WT,u-PA-/and t-PA-/cells,but about two-fold higher for PAI-1-/cells. Plasminogen activation was impaired by addition of the lysine analogue 6-aminohexanoic acid, and by addition of t-PA and u-PA neutralizing antibodies, suggesting that it depends on binding to cell surface COOH-terminal lysine residues, and on plasminogen activator activity. Morphological alterations consistent with apoptosis were observed much earlier in PAI-1-/than in WT VSMC. Without addition of plasminogen, the apoptotic index was similar for all four cell types, whereas after incubation with physiological plasminogen concentrations, it was greater in PAI-1-/VSMC, as compared to WT, t-PA-/or u-PA-/VSMC. Furthermore, the apoptotic rate paralleled the release of plasmin. Thus, plasmin-mediated apoptosis of VSMC occurs via plasminogen activation by either t-PA or u-PA and is impaired by PAI-1.Keywords
Funding Information
- Institut National de la Santé et de la Recherche Médicale (INSERM, France)
- Leducq Foundation (Transatlantic Networks)
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