Cytosolic phospholipase A^sub 2^-[alpha] is an early apoptotic activator in PEDF-induced endothelial cell apoptosis

Pigment epithelium-derived factor (PEDF) is an intrinsic antiangiogenic 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 the present study, we investigated the signaling role of cytosolic calcium-dependent phospholipase A...-α (cPLA...-α) to bridge p38 MAPK and PPAR-... activation. PEDF induced cPLA...-α activation in HUVECs and in endothelial cells in chemical burn-induced vessels on mouse cornea. The cPLA...-α activation is evident from the phosphorylation and nuclear translocation of cPLA...-α as well as arachidonic acid release and the cleavage of PED6, a synthetic PLA... 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 cPLA... inhibitor and small interfering RNA targeting cPLA...-α. Our observation not only establishes the signaling role of cPLA...-α but also for the first time demonstrates the sequential activation of p38 MAPK, cPLA...-α, PPAR-..., and p53 as the mechanism of PEDF-induced endothelial cell apoptosis. (ProQuest: ... denotes formulae/symbols omitted.)