on April 27, 2006
Published online before print April 27, 2006, doi: 10.1161/01.ATV.0000223875.14120.93
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Submitted on March 30, 2006
Accepted on April 7, 2006
Protection of Endothelial Survival by Peroxisome Proliferator-Activated Receptor-
Mediated 14-3-3 Upregulation
Jun-Yang Liou ;
From the Vascular Biology Research Center (J.-Y.L., S.L., D.G., K.K.W.), Brown Foundation Institute of Molecular Medicine, and Division of Hematology (J.-Y.L., S.L., D.G., N.M.-A., K.K.W.), Department of Internal Medicine, Medical School, University of Texas Health Science Center at Houston.
* To whom correspondence should be addressed. E-mail: kenneth.k.wu{at}uth.tmc.edu.
Objective--To determine the role of prostacyclin (PGI2) in protecting endothelial cells (ECs) from apoptosis and elucidate the protective mechanism.
Methods and Results--To evaluate the effect of PGI2 on EC survival, we treated ECs with Ad-COPI, which augmented selectively PGI2 production or carbaprostacyclin (cPGI2) followed by H2O2 for 4 hours. Ad-COPI inhibited annexin V-positive cells and blocked caspase 3 activation. cPGI2 inhibited apoptosis in a concentration-dependent manner. L-165041 had a similar effect, suggesting the involvement of peroxisome proliferator-activated receptor-
(PPAR). ECs expressed functional PPAR. PPAR overexpression enhanced whereas PPAR knockdown by small interfering RNA abrogated the antiapoptotic action of cPGI2 and L-165041. Our results show for the first time that PGI2 stimulated 14-3-3
expression via PPAR activation. cPGI2 and L-165041 induced binding oaf PPAR to PPAR response elements located between -1426 and -1477 of 14-3-3 promoter region, thereby activating 14-3-3 promoter activity and protein expression. Upregulation of 14-3-3 proteins resulted in an increase in Bad binding to 14-3-3 and a reduction in Bad translocation to mitochondria.
Conclusions--PGI2 protects ECs from H2O2-induced apoptosis by inducing PPAR binding to 14-3-3 promoter, thereby upregulating 14-3-3 protein expression. Elevated 14-3-3 augments Bad sequestration and prevents Bad-triggered apoptosis.
Key words: apoptosis • endothelial cells • PPAR
, prostacyclin •
14-3-3
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