PEDF induces p53-mediated apoptosis through PPAR gamma signaling in human umbilical vein endothelial cells.

Abstract:

OBJECTIVE:Pigment epithelial-derived factor (PEDF) is a potent anti-angiogenic factor whose effects are partially mediated through the induction of endothelial cell apoptosis. The pathway mediating endothelial cell apoptosis has not been fully established. Here we investigated the participation of peroxisome proliferator-activated receptor gamma (PPARgamma) and p53 in the apoptosis of human umbilical vein endothelial cells (HUVECs). METHODS AND RESULTS:HUVECs pretreated with either PPARgamma antagonist or PPARgamma small interfering RNA (siRNA) suppressed PEDF-induced apoptosis as determined by TUNEL assay, annexin V-FITC/PI staining, and cleavage of procaspase-8, -9, -3. PEDF sequentially induced PPARgamma and p53 expression as observed in immunoblotting and immunofluoresence assays. PEDF also increased the transcriptional activity of PPARgamma as evident from electromobility shift assays, and p53 as determined by the phosphorylation and acetylation of p53 and the induction of Bax. The induction of p53 by PEDF was abolished by either PPARgamma antagonist or PPARgamma siRNA. PEDF-mediated HUVEC apoptosis and cleavage of procaspases were significantly attenuated by p53 siRNA. CONCLUSIONS:Our observations indicate that PEDF induces HUVECs apoptosis through the sequential induction of PPARgamma and p53 overexpression. With the growing interest in anti-angiogenesis as a novel approach to cancer therapy, defining the mechanism of PEDF-mediated HUVEC apoptosis may facilitate the development of new therapeutics.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Ho TC,Chen SL,Yang YC,Liao CL,Cheng HC,Tsao YP

doi

10.1016/j.cardiores.2007.06.032

subject

Has Abstract

pub_date

2007-11-01 00:00:00

pages

213-23

issue

2

eissn

0008-6363

issn

1755-3245

pii

S0008-6363(07)00311-2

journal_volume

76

pub_type

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    doi:

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