15-Deoxy-Δ(12,14)-prostaglandin J2 induces vascular endothelial cell apoptosis through the sequential activation of MAPKS and p53

Tsung Chuan Ho, Show Li Chen, Yuh Cheng Yang, Chia Yi Chen, Fang Ping Feng, Jui Wen Hsieh, Huey Chuan Cheng, Yeou Ping Tsao*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

31 Scopus citations

Abstract

15-Deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2) is a potent anti-angiogenic factor and induces endothelial cell apoptosis, although the mechanism remains unclear. In this study, 15d-PGJ2 was found to increase p53 levels of the human umbilical vein endothelial cells by stabilizing p53. Both 15d-PGJ2-induced apoptosis and the induction of p21Waf1 and Bax can be abolished by p53 small interfering RNA but not by peroxisome proliferator-activated receptor γ inhibitors. Moreover, 15d-PGJ2 activated JNK and p38 MAPK while inducing p53 phosphorylation at sites responsible for p53 activity. JNK inhibitor (SP600125) or p38 MAPK inhibitor (SB203580) pretreatment attenuated 15d-PGJ 2-mediated apoptosis and suppressed the p21Waf1 and Bax expressions without affecting p53 protein accumulation. Pretreatment with SP600125 partially prevented the phosphorylation of p53 at serines 33 and 392 induced by 15d-PGJ2. 15d-PGJ2 was also found to induce reactive oxygen species generation and partially blocked nuclear factor-κB activity. Pretreatment with antioxidant N-acetylcysteine prevented the p53 accumulation, the phosphorylations of JNK and p38 MAPK, the inhibition of NF-κB activity, as well as the apoptosis induced by 15d-PGJ2. Using a mouse model of corneal neovascularization, it was demonstrated in vivo that 15d-PGJ2 induced reactive oxygen species generation, activated JNK and p38 MAPK, induced p53 accumulation/phosphorylation, and induced vascular endothelial cell apoptosis, which could be abolished by N-acetylcysteine, SP600125, SB203580, or a virus-derived amphipathic peptides-based p53 small interfering RNA. This is the first study that 15d-PGJ2 induces vascular endothelial cell apoptosis through the signaling of JNK and p38 MAPK-mediated p53 activation both in vitro and in vivo, further establishing the potential of 15d-PGJ2 as an anti-angiogenesis agent.

Original languageEnglish
Pages (from-to)30273-30288
Number of pages16
JournalJournal of Biological Chemistry
Volume283
Issue number44
DOIs
StatePublished - 31 10 2008
Externally publishedYes

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