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Inhibition of apoptosis and caspase‐3 in vascular smooth muscle cells by plasminogen activator inhibitor type‐1
Author(s) -
Chen Yabing,
Kelm Robert J.,
Budd Ralph C.,
Sobel Burton E.,
Schneider David J.
Publication year - 2004
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.20058
Subject(s) - serpin , apoptosis , plasminogen activator , plasminogen activator inhibitor 1 , microbiology and biotechnology , vascular smooth muscle , poly adp ribose polymerase , chemistry , caspase 3 , caspase 9 , caspase , biology , endocrinology , programmed cell death , biochemistry , polymerase , enzyme , gene , smooth muscle
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.

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