title: Induction of apoptosis in vascular cells by plasminogen activator inhibitor-1 and high molecular weight kininogen correlates with their anti-adhesive properties.
abstract: Plasminogen activator inhibitor-1 (PAI-1) and two-chain high molecular weight kininogen (HKa) exert anti-adhesive properties in vitronectin-dependent cell adhesion. Here, the hypothesis was tested that these anti-adhesive components promote apoptosis in vascular cells. PAI-1 or HKa induced a 2- to 3-fold increase in apoptosis of human umbilical-vein endothelial cells (HUVEC) and vascular smooth muscle cells (VSMC) adherent to vitronectin, as determined by annexin V-FACS assay, similar to alphav-integrin inhibitor cyclo-(Arg-Gly-Asp-D-Phe-Val)-peptide (cRGDfV). Apoptosis occurred after 12 h incubation and was attributable to caspase 3 activation that in turn induced DNA fragmentation. Induction of apoptosis strongly correlated with the anti-adhesive effect of PAI-1 and HKa on these cells. In contrast, PAI-1 and HKa did not affect fibronectin-dependent adhesion or cell survival. uPA did not influence apoptosis in vitronectin- or fibronectin-adherent cells. In atherosclerotic vessel sections, congruent distribution of vitronectin, PAI-1, HK, and of components of the urokinase plasminogen activator/receptor system with apoptotic cells lining foam cell lesions was demonstrated by immunostaining. These results indicate that inhibition of vitronectin-dependent cell adhesion through PAI-1 and HKa correlates with apoptosis induction in vascular cells mediated through the caspase 3 pathway. Co-distribution of apoptosis with plasminogen activation system components in atherosclerosis exemplifies the significance of anti-adhesive mechanisms and apoptosis for tissue remodeling, such as in neointima development.
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, Justus Liebig University, Gaffkystrasse 11, D-35392 Giessen, Germany.
authors.forename: Nadia
authors.initials: N
authors.lastname: Al-Fakhri
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Chavakis
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmidt-Wöll
authors.forename: Bei
authors.initials: B
authors.lastname: Huang
authors.forename: Sanjay M
authors.initials: SM
authors.lastname: Cherian
authors.forename: Yuri V
authors.initials: YV
authors.lastname: Bobryshev
authors.forename: Reginald S A
authors.initials: RS
authors.lastname: Lord
authors.forename: Norbert
authors.initials: N
authors.lastname: Katz
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Preissner
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001161:Arteriosclerosis / Q000503:physiopathology; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology*; D005353:Fibronectins / Q000494:pharmacology; D006801:Humans; D007704:Kininogens / Q000494:pharmacology*; D008970:Molecular Weight; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D017395:Plasminogen Activator Inhibitor 1 / Q000494:pharmacology*; D019096:Vitronectin / Q000494:pharmacology
chemical_list: D005353:Fibronectins; D007704:Kininogens; D017395:Plasminogen Activator Inhibitor 1; D019096:Vitronectin