Cytosolic phospholipase A2-α is an early apoptotic activator in PEDF-induced endothelial cell apoptosis
Journal
American Journal of Physiology - Cell Physiology
Journal Volume
296
Journal Issue
2
Pages
C273-C284
Date Issued
2009
Author(s)
Abstract
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-7), and p53. In the present study, we investigated the signaling role of cytosolic calcium-dependent phospholipase A2-α (cPLA2-α) to bridge p38 MAPK and PPAR-7 activation. PEDF induced cPLA2-α activation in HUVECs and in endothelial cells in chemical burn-induced vessels on mouse cornea. The cPL2-αactivation is evident from the phosphorylation and nuclear translocation of cPL2-αas well as arachidonic acid release and the cleavage of PED6, a synthetic PLA2 substrate. Such activation can be abolished by p38 MAPK inhibitor. The PEDF-induced PPAR-γ activation, p53 expression, caspase-3 activity, and apoptosis can be abolished by both cPLA2 inhibitor and small interfering RNA targeting cPL2-α. Our observation not only establishes the signaling role of cPL2-αbut also for the first time demonstrates the sequential activation of p38 MAPK, cPLA2-α PPAR-γ, and p53 as the mechanism of PEDF- induced endothelial cell apoptosis. Copyright ? 2009 the American Physiological Society.
Subjects
P38 mitogen-activated protein kinase; Peroxisome proliferator-activated receptor-γ; Pigment epithelium-derived factor
SDGs
Other Subjects
arachidonic acid; caspase 3; cytosolic phospholipase A2; mitogen activated protein kinase; mitogen activated protein kinase inhibitor; peroxisome proliferator activated receptor gamma; pigment epithelium derived factor; protein p53; small interfering RNA; synaptophysin; CASP3 protein, human; caspase 3; eye protein; mitogen activated protein kinase p38; nerve growth factor; peroxisome proliferator activated receptor gamma; phosphodiesterase inhibitor; phospholipase A2 group IV; pigment epithelium derived factor; pigment epithelium-derived factor; PLA2G4A protein, human; Pla2g4a protein, mouse; protein kinase inhibitor; protein p53; recombinant protein; serine; serine proteinase inhibitor; TP53 protein, human; animal cell; animal experiment; animal tissue; apoptosis; article; Bagg albino mouse; chemical burn; controlled study; cornea vascularization; endothelium cell; enzyme activity; enzyme substrate; human; human cell; mouse; nonhuman; priority journal; protein phosphorylation; signal transduction; umbilical vein; active transport; animal; cell culture; chemically induced disorder; cornea neovascularization; disease model; drug antagonism; drug effect; enzymology; eye burn; genetics; metabolism; pathology; phosphorylation; RNA interference; time; Active Transport, Cell Nucleus; Animals; Apoptosis; Arachidonic Acid; Burns, Chemical; Caspase 3; Cells, Cultured; Corneal Neovascularization; Disease Models, Animal; Endothelial Cells; Eye Burns; Eye Proteins; Group IV Phospholipases A2; Humans; Mice; Mice, Inbred BALB C; Nerve Growth Factors; p38 Mitogen-Activated Protein Kinases; Phosphodiesterase Inhibitors; Phosphorylation; PPAR gamma; Protein Kinase Inhibitors; Recombinant Proteins; RNA Interference; Serine; Serpins; Signal Transduction; Time Factors; Tumor Suppressor Protein p53
Type
journal article