Submitted on August 22, 2008
Revised on September 16, 2008
Accepted on December 4, 2008
Cytosolic phospholipase A2-alpha is an early apoptotic activator in PEDF-induced endothelial cell apoptosis
Tsung-Chuan Ho1, Show-Li Chen2, Yuh-Cheng Yang3, Tzu-Hsiu Lo4, Jui-Wen Hsieh3, Huey-Chuan Cheng1, and Yeou-Ping Tsao1*
1 Mackay Memorial Hospital
2 National Taiwan University
3 Taipei Medical University
4 National Defense Medical Center
* To whom correspondence should be addressed. E-mail: yptsao{at}yahoo.com.
Pigment epithelial-derived factor (PEDF) is an intrinsic anti-angioenic factor and a potential therapeutic agent. Previously, we discovered the mechanism of PEDF-induced apoptosis of human umbilical vein endothelial cells (HUVECs) as sequential induction/activation of p38 mitogen-activated protein kinase (MAPK), peroxisome proliferator-activated receptor gamma (PPAR
) and p53. In this study, we investigated the signaling role of cytosolic calcium-dependent phospholipase A2-alpha (cPLA2-
) to bridge p38 MAPK and PPAR activation. PEDF induced cPLA2- activation in HUVECs and in ECs in chemical burn-induced vessels on mouse cornea. The cPLA2- activation is evident from the phosphorylation and nuclear translocation of cPLA2- as well as arachidonic acid (AA) release and the cleavage of PED6, which a synthetic PLA2 substrate. Such activation can be abolished by p38 MAPK inhibitor. The PEDF-induced PPAR activation, p53 expression, caspase-3 activity and apoptosis can be abolished by both cPLA2 inhibitor and small interfering RNA targeting cPLA2-. Our observation not only establishes the signaling role of cPLA2- but also for the first time demonstrate the sequential activation of p38 MAPK, cPLA2-,PPAR and p53 as the mechanism of PEDF-induced EC apoptosis.
