Inhibition of apoptosis and caspase‐3 in vascular smooth muscle cells by plasminogen activator inhibitor type‐1

Authors:
  • RKRobert J. Kelm
    Robert J. Kelm
Publisher website
Google Scholar
Abstract
Increased expression of plasminogen activator inhibitor type 1 (PAI‐1) is associated with decreased apoptosis of neoplastic cells. We sought to determine whether PAI‐1 alters apoptosis in vascular smooth muscle cells (VSMC) and, if so, by what mechanisms. A twofold increase in the expression of PAI‐1 was induced in VSMC from transgenic mice with the use of the SM‐22α gene promoter (SM22‐PAI+). Cultured VSMC from SM22‐PAI+ mice were more resistant to apoptosis induced by tumor necrosis factor plus phorbol myristate acetate or palmitic acid compared with VSMC from negative control littermates. Both wild type (WT) and a stable active mutant form of PAI‐1 (Active) inhibited caspase‐3 amidolytic activity in cell lysates while a serpin‐defective mutant (Mut) PAI‐1 did not. Similarly, both WT and Active PAI‐1 decreased amidolytic activity of purified caspase‐3, whereas Mut PAI‐1 did not. WT but not Mut PAI‐1 decreased the cleavage of poly‐[ADP‐ribose]‐polymerase (PARP), the physiological substrate of caspase‐3. Noncovalent physical interaction between caspase‐3 and PAI‐1 was demonstrable with the use of both qualitative and quantitative in vitro binding assays. High affinity binding was eliminated by mutations that block PAI‐1 serpin activity. Accordingly, attenuated apoptosis resulting from elevated expression of PAI‐1 by VSMC may be attributable, at least in part, to reversible inhibition of caspase‐3 by active PAI‐1.

This publication has 55 references indexed in Scilit: