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Exogenous Tissue Inhibitor of Metalloproteinase‐1 Promotes Endothelial Cell Survival Through Activation of the Phosphatidylinositol 3‐Kinase/Akt Pathway
Author(s) -
BOULDAY GWÉNOLA,
FITAU JULIETTE,
COUPEL STÉPHANIE,
SOULILLOU JEANPAUL,
CHARREAU BÉATRICE
Publication year - 2004
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1329.004
Subject(s) - wortmannin , microbiology and biotechnology , protein kinase b , pi3k/akt/mtor pathway , ly294002 , signal transduction , kinase , phosphorylation , apoptosis , phosphatidylinositol , chemistry , cancer research , biology , biochemistry
A bstract : Control of molecular targets and signaling pathways which improve endothelial cell survival may be an attractive concept for interfering with dysregulated vascular injury and remodeling, a key mechanism for transplant arteriosclerosis and chronic allograft rejection. In addition to inhibiting matrix metalloproteinase activity, it has been suggested by recent studies that the tissue inhibitor of metalloproteinase (TIMP)‐1 may inhibit apoptosis in various cell types. The present work examines the possibility that TIMP‐1 belongs to a protective pathway via antiapoptotic properties and investigates the signaling pathway mediated by TIMP‐1 in human ECs. We demonstrate that exogenous, recombinant, TIMP‐1 efficiently prevents apoptosis induced by TNFα in cycloheximide‐sensitized ECs. The antiapoptotic effect of TIMP‐1 was dose‐dependent and a maximal effect of TIMP‐1 (30% protection) was reached using 250 ng/mL of recombinant TIMP‐1. We present evidence that TIMP‐1 induces activation of PI3‐kinase but not NFκB pathway in ECs. Our findings further indicate that TIMP‐1‐induced EC survival is mediated through activation of PI3‐kinase pathway and the downstream phosphorylation of Akt kinase. Blocking the PI3‐kinase pathway with wortmannin or LY294002 restores TNFα‐mediated EC death. In conclusion, our findings suggest that TIMP‐1, generated upon inflammation, acts as an antiapoptotic molecule that can prevent EC apoptosis through activation of the PI3‐kinase and phosphorylation of the Akt kinase.