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Nonsteroidal Anti-Inflammatory Drugs Induced Endothelial Apoptosis by Perturbing Peroxisome Proliferator-Activated Receptor- Transcriptional Pathway

The National Health Research Institutes, Zhunan, Miaoli, Taiwan (J.-Y.L., C.-C.W., B.-R.C., L.B.Y., K.K.W.); National Tsing Hua University, Hsinchu, Taiwan (B.-R.C., K.K.W.); and University of Texas Health Science Center, Houston, Texas (J.-Y.L., K.K.W.)

Recent studies have shown that use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with an increased risk of myocardial infarction. To explore whether NSAIDs may induce endothelial apoptosis and thereby enhance atherothrombosis, we treated human umbilical vein endothelial cells (HUVECs) with sulindac sulfide (SUL), indomethacin (IND), aspirin (ASA), or sodium salicylate (NaS), and we analyzed apoptosis. SUL and/or IND significantly increased annexin V-positive cells, cleaved poly(ADP-ribose) polymerase (PARP) and caspase-3. ASA and NaS at 1 mM did not induce PARP cleavage or caspase-3 and at 5 mM, ASA but not NaS increased apoptosis. Because peroxisome proliferator-activated receptor -mediated 14-3-3 up-regulation was reported to play a crucial role in protecting against apoptosis, we determined whether NSAIDs suppress this transcriptional pathway. SUL, IND, and ASA (5 mM) suppressed PPAR and 14-3-3 proteins in a manner parallel to PARP cleavage. Neither ASA nor NaS at 1 mM interfered with PPAR or 14-3-3 expression. SUL inhibited PPAR promoter activity, which correlated with 14-3-3 promoter suppression. Suppression of 14-3-3 was associated with increased Bad translocation to mitochondria. Neither carbaprostacylin nor 4-(3-(2-propyl-3-hydroxy-4-acetyl)-phenoxy)propyloxyphenoxy acetic acid (L-165041) prevented HUVECs from SUL-induced apoptosis. Because of suppression of ectopic PPAR by sulindac, adenoviral PPAR transduction failed to restore 14-3-3 or prevent PPAR cleavage. Our findings suggest that NSAIDs, but not aspirin (<1 mM) induce endothelial apoptosis via suppression of PPAR-mediated 14-3-3 expression.

Received for publication June 11, 2008.

Accepted for publication August 4, 2008.

Address correspondence to: Dr. Kenneth K. Wu, National Health Research Institutes, 35 Keyan Rd., Zhunan Township, Miaoli County 350, Taiwan. E-mail: kkgo{at}nhri.org.tw