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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1481.)
© 2006 American Heart Association, Inc.

Vascular Biology

Protection of Endothelial Survival by Peroxisome Proliferator-Activated Receptor- Mediated 14-3-3 Upregulation

Jun-Yang Liou; Sang Lee; Dipak Ghelani; Nevenka Matijevic-Aleksic; Kenneth K. Wu

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.

Correspondence to Kenneth K. Wu, Vascular Biology Research Center, Brown Foundation Institute of Molecular Medicine, and Division of Hematology, Department of Internal Medicine, Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030-1503. 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-COX1/PGIS (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.

We postulated that EC-synthesized PGI₂ protects ECs from apoptosis. Results show that PGI₂ generated by transduction with an adenoviral vector containing a bicistronic cyclooxygenase-1 and PGI₂ synthase construct (Ad-COPI) or synthetic carbaprostacyclin (cPGI₂) suppressed H₂O₂-induced EC apoptosis by a novel PPAR-mediated 14-3-3 transcriptional upregulation.

Key Words: apoptosis • endothelial cells • PPAR, prostacyclin • 14-3-3

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