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Am J Physiol Cell Physiol 296: C273-C284, 2009. First published December 17, 2008; doi:10.1152/ajpcell.00432.2008
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VASCULAR BIOLOGY

Cytosolic phospholipase A2-{alpha} is an early apoptotic activator in PEDF-induced endothelial cell apoptosis

Tsung-Chuan Ho,1 Show-Li Chen,2 Yuh-Cheng Yang,1,4 Tzu-Hsiu Lo,5 Jui-Wen Hsieh,3,6 Huey-Chuan Cheng,6 and Yeou-Ping Tsao1,5,6

Departments of 1Medical Research and 6Ophthalmology, Mackay Memorial Hospital; 2Department of Microbiology, School of Medicine, National Taiwan University; 3Department of Ophthalmology and 4School of Medicine, Taipei Medical University; and 5Department of Microbiology and Immunology, The National Defense Medical Center, Taipei, Taiwan

Submitted 22 August 2008 ; accepted in final form 4 December 2008

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-{gamma}), and p53. In the present study, we investigated the signaling role of cytosolic calcium-dependent phospholipase A2-{alpha} (cPLA2-{alpha}) to bridge p38 MAPK and PPAR-{gamma} activation. PEDF induced cPLA2-{alpha} activation in HUVECs and in endothelial cells in chemical burn-induced vessels on mouse cornea. The cPLA2-{alpha} activation is evident from the phosphorylation and nuclear translocation of cPLA2-{alpha} as 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-{gamma} activation, p53 expression, caspase-3 activity, and apoptosis can be abolished by both cPLA2 inhibitor and small interfering RNA targeting cPLA2-{alpha}. Our observation not only establishes the signaling role of cPLA2-{alpha} but also for the first time demonstrates the sequential activation of p38 MAPK, cPLA2-{alpha}, PPAR-{gamma}, and p53 as the mechanism of PEDF-induced endothelial cell apoptosis.

pigment epithelium-derived factor; p38 mitogen-activated protein kinase; peroxisome proliferator-activated receptor-{gamma}


Address for reprint requests and other correspondence: Y.-P. Tsao, Dept. of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan (e-mail: yptsao{at}yahoo.com)






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