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

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 γ (PPARγ) and p53 in the apoptosis of human umbilical vein endothelial cells (HUVECs). Methods and results: HUVECs pretreated with either PPARγ antagonist or PPARγ 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 PPARγ and p53 expression as observed in immunoblotting and immunofluoresence assays. PEDF also increased the transcriptional activity of PPARγ 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 PPARγ antagonist or PPARγ 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 PPARγ 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.