Received for publication June 13, 2008.
Revised August 3, 2008.
Accepted for publication August 4, 2008.

Nonsteroidal Anti-inflammatory Drugs Induced Endothelial Apoptosis by Perturbing PPAR- Transcriptional Pathway

Abstract

Recent studies have shown that use of NSAIDs is associated with an increased risk of myocardial infarction. To explore if 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 analyzed apoptosis. SUL and/or IND significantly increased annexin V positive cells, cleaved 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. As peroxisome proliferator-activated receptor (PPAR)-mediated 14-3-3 upregulation was reported to play a crucial role in protecting against apoptosis, we determined whether NSAIDs suppress this transcriptional pathway. SUL, IND and ASA (5mM) 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 PGI₂ nor L-165041 prevented HUVEC from SUL-induced apoptosis. Adenoviral PPAR transduction failed to restore 14-3-3 or prevent PPAR cleavage due to suppression of ectopic PPAR by sulindac. Our findings suggest that NSAIDs but not aspirin (<1 mM) induce endothelial apoptosis via suppression of PPAR-mediated 14-3-3 expression.

Key words: PPARs, Eicosanoids, Mechanisms of cell killing/apoptosis