Nonsteroidal Anti-Inflammatory Drugs Induced Endothelial Apoptosis by Perturbing Peroxisome Proliferator-Activated Receptor-δ Transcriptional Pathway
Nonsteroidal Anti-Inflammatory Drugs Induced Endothelial Apoptosis by Perturbing Peroxisome Proliferator-Activated Receptor-δ Transcriptional Pathway
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DOI：
10.1124/mol.108.049569
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发表时间：
2008-11-01
影响因子：
3.6
通讯作者：
Wu, Kenneth K.
中科院分区：
文献类型：
--
作者：
Liou, Jun-Yang;Wu, Chia-Ching;Wu, Kenneth K.
最近的研究表明，使用非甾体抗炎药（NSAID）与心肌梗死的风险增加有关。为了探索NSAID是否可以诱导内皮细胞凋亡，从而增强动脉粥样硬化血栓形成，我们用舒林酸硫化物（SUL），吲哚美辛（IND），阿司匹林（阿萨）或水杨酸钠（NaS）处理人脐静脉内皮细胞（HUVECs），并分析凋亡。SUL和/或IND显著增加膜联蛋白V阳性细胞，裂解的聚（ADP-核糖）聚合酶（PARP）和半胱天冬酶-3。阿萨和NaS在1 mM时不诱导PARP裂解或半胱天冬酶-3，在5 mM时，阿萨而不是NaS增加细胞凋亡。由于过氧化物酶体增殖物激活受体δ介导的14-3-3 β上调被报道在防止细胞凋亡中起关键作用，我们确定了NSAID是否抑制该转录途径。SUL、IND和阿萨（5 mM）以与PARP裂解平行的方式抑制了PPAR δ和14-3-3蛋白。阿萨和NaS在1 mM时均不干扰PPAR δ或14-3-3 β的表达。SUL抑制PPAR δ启动子活性，这与14-3-3 β启动子抑制相关。14-3-3 β的抑制与Bad易位到线粒体的增加有关。卡前列环素和4-（3-（2-丙基-3-羟基-4-乙酰基）苯氧基）丙氧基苯氧基乙酸（L-165041）均不能阻止HUVEC发生SUL诱导的凋亡。由于舒林酸对异位PPARdelta的抑制，腺病毒PPARdelta转导未能恢复14-3-3 β或阻止PPARdelta裂解。我们的研究结果表明，非甾体抗炎药，而不是阿司匹林（< 1 mM）通过抑制过氧化物酶体增殖物激活受体δ介导的14-3-3 β表达诱导内皮细胞凋亡。
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 delta-mediated 14-3-3 epsilon 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 delta and 14-3-3 proteins in a manner parallel to PARP cleavage. Neither ASA nor NaS at 1 mM interfered with PPAR delta or 14-3-3 epsilon expression. SUL inhibited PPAR delta promoter activity, which correlated with 14-3-3 epsilon promoter suppression. Suppression of 14-3-3 epsilon 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 delta by sulindac, adenoviral PPAR delta transduction failed to restore 14-3-3 epsilon or prevent PPAR cleavage. Our findings suggest that NSAIDs, but not aspirin (< 1 mM) induce endothelial apoptosis via suppression of PPAR delta-mediated 14-3-3 epsilon expression.