Raloxifene analogue LY117018 suppresses oxidative stress-induced endothelial cell apoptosis through activation of ERK1/2 signaling pathway.
Raloxifene analogue LY117018 suppresses oxidative stress-induced endothelial cell apoptosis through activation of ERK1/2 signaling pathway.
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DOI：
10.1016/j.ejphar.2008.04.052
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发表时间：
2008-07
影响因子：
5
通讯作者：
Jing Yu;M. Eto;K. Kozaki;M. Akishita;T. Okabe;Y. Ouchi
中科院分区：
文献类型：
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作者：
Jing Yu;M. Eto;K. Kozaki;M. Akishita;T. Okabe;Y. Ouchi
一种选择性雌激素受体调节剂雷洛昔芬，已被证明可以减少相对高危的绝经后骨质疏松症妇女的心血管事件。然而，雷洛昔芬对心血管器官发挥药理学作用的机制尚未完全阐明。本研究旨在观察雷洛昔芬类似物6-羟基-2-（对羟基苯基）-苯并（B）噻吩-3-基-对（2-（吡咯烷基）乙氧基苯基酮（LY 117018）是否能抑制血管内皮细胞凋亡，并阐明其信号通路。LY 117018显著抑制过氧化氢诱导的牛颈动脉内皮细胞凋亡。LY 117018的抗凋亡作用可被雌激素受体拮抗剂7α，7 β-（9[（4，4，5，5，5-Pentafluoropentyl）sulfinyl]nonyl）estra-1，3，5（10）-triene-3，17-diol（ICI 182，780）阻断。丝裂原活化蛋白激酶（MAPK），包括p38、c-Jun N-末端激酶（JNK）和细胞外信号调节蛋白激酶1/2（ERK 1/2）以及Akt，已被证明作为凋亡或抗凋亡信号。检测p38、JNK、ERK 1/2和Akt的磷酸化。LY 117018增加ERK 1/2磷酸化，但不增加p38、JNK或Akt的磷酸化。LY 117018的抗凋亡作用可被ERK 1/2上游抑制剂2-[2′-氨基-3 ′-甲氧基苯基]-氧杂萘-4-酮（PD 98059）阻断。LY 117018刺激ERK 1/2磷酸化的增加，ICI 182，780减弱了这种作用。LY 117018对ERK/1/2的激活作用不受转录抑制剂放线菌素D的抑制。这些结果表明，雌激素受体和ERK 1/2信号通路参与LY 117018在血管内皮细胞中的抗凋亡作用。
A selective estrogen receptor modulator, raloxifene, has been shown to reduce cardiovascular events in relatively high-risk postmenopausal women with osteoporosis. However, the mechanisms by which raloxifene exerts a pharmacological effect on cardiovascular organs have not been fully elucidated. The present study was designed to examine whether the raloxifene analogue, 6-hydroxy-2-(p-hydroxyphenyl)-benzo(b) thien-3-yl-p-(2-(pyrrolidinyl)ethoxy phenyl ketone (LY117018), could inhibit apoptosis and to clarify the signaling pathway in vascular endothelial cells. LY117018 significantly inhibited hydrogen peroxide-induced apoptosis in bovine carotid artery endothelial cells. The anti-apoptotic effect of LY117018 was abolished by an estrogen receptor antagonist, 7α,7β-(9[(4,4,5,5,5-Pentafluoropentyl)sulfinyl]nonyl) estra-1,3,5(10)-triene-3,17-diol (ICI 182,780). Mitogen-activated protein kinases (MAPK), including p38, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase1/2 (ERK1/2), and Akt, have been shown to act as apoptotic or anti-apoptotic signals. Phosphorylation of p38, JNK, ERK1/2 and Akt was examined. LY117018 increased ERK1/2 phosphorylation but did not enhance the phosphorylation of p38, JNK, or Akt. The anti-apoptotic effect of LY117018 was prevented by treatment with 2-[2′-amino-3′-methoxyphenyl]-oxanaphthalen-4-one (PD98059), an upstream inhibitor of ERK1/2. LY117018 stimulated an increase in ERK1/2 phosphorylation, which was diminished by ICI 182,780. The activation of ERK/1/2 by LY117018 was not inhibited by the transcription inhibitor, actinomycin D. These results suggest that estrogen receptors and the ERK1/2 signaling pathway are involved in the anti-apoptotic action of LY117018 in vascular endothelial cells.