Protection of endothelial survival by peroxisome proliferator-activated receptor-δ mediated 14-3-3 upregulation
Protection of endothelial survival by peroxisome proliferator-activated receptor-δ mediated 14-3-3 upregulation
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DOI：
10.1161/01.atv.0000223875.14120.93
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发表时间：
2006-07-01
影响因子：
8.7
通讯作者：
Wu, Kenneth K.
中科院分区：
文献类型：
--
作者：
Liou, Jun-Yang;Lee, Sang;Wu, Kenneth K.
目的-确定前列环素（PGI（2））在保护内皮细胞（EC）免于凋亡中的作用并阐明保护机制。方法和结果-为了评估PGI（2）对EC存活的影响，我们用Ad-COX 1/PGIS（Ad-COPI）处理EC，其选择性地增加PGI（2）的产生或卡前列环素（cPGI（2）），随后用H2 O2处理4小时。Ad-COPI抑制膜联蛋白V阳性细胞并阻断半胱天冬酶3活化。cPGI（2）呈浓度依赖性抑制细胞凋亡。L-165041具有类似的作用，表明过氧化物酶体增殖物激活受体-δ（PPAR δ）参与。内皮细胞表达功能性过氧化物酶体增殖物激活受体δ。PPAR δ过表达增强，而小干扰RNA敲低PPAR δ则消除了cPGI（2）和L-165041的抗凋亡作用。我们的研究结果首次表明，PGI（2）通过激活PPAR δ刺激14-3-3 β的表达。cPGI（2）和L-165041可诱导PPARdelta与14-3-3 β启动子区-1426和-1477之间的PPAR反应元件结合，从而激活14-3-3 β启动子活性和蛋白表达。结论：PGI（2）通过诱导PPAR δ与14 - 3 - 3 β启动子结合，从而上调14 - 3 - 3 β蛋白的表达，保护内皮细胞免受H2 O2诱导的凋亡。升高的14-3-3激酶增强Bad隔离并防止Bad触发的细胞凋亡。
Objective - To determine the role of prostacyclin (PGI(2)) in protecting endothelial cells (ECs) from apoptosis and elucidate the protective mechanism.Methods and Results - To evaluate the effect of PGI(2) on EC survival, we treated ECs with Ad-COX1/PGIS (Ad-COPI), which augmented selectively PGI(2) production or carbaprostacyclin (cPGI(2)) followed by H2O2 for 4 hours. Ad-COPI inhibited annexin V - positive cells and blocked caspase 3 activation. cPGI(2) inhibited apoptosis in a concentration-dependent manner. L-165041 had a similar effect, suggesting the involvement of peroxisome proliferator-activated receptor-delta (PPAR delta). ECs expressed functional PPAR delta. PPAR delta overexpression enhanced whereas PPAR delta knockdown by small interfering RNA abrogated the antiapoptotic action of cPGI(2) and L-165041. Our results show for the first time that PGI(2) stimulated 14-3-3 epsilon expression via PPAR delta activation. cPGI(2) and L-165041 induced binding oaf PPAR delta to PPAR response elements located between -1426 and -1477 of 14-3-3 epsilon promoter region, thereby activating 14-3-3 epsilon promoter activity and protein expression. Upregulation of 14-3-3 epsilon proteins resulted in an increase in Bad binding to 14-3-3 epsilon and a reduction in Bad translocation to mitochondria.Conclusions - PGI(2) protects ECs from H2O2-induced apoptosis by inducing PPAR delta binding to 14-3-3 epsilon promoter, thereby upregulating 14-3-3 epsilon protein expression. Elevated 14-3-3 epsilon augments Bad sequestration and prevents Bad-triggered apoptosis.