Role of prostacyclin signaling in endothelial production of soluble amyloid precursor protein-α in cerebral microvessels
Role of prostacyclin signaling in endothelial production of soluble amyloid precursor protein-α in cerebral microvessels
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前列环素信号在脑微血管中可溶性淀粉样蛋白-α的内皮生成中的作用
DOI：
10.1177/0271678x15618977
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发表时间：
2017-01-01
影响因子：
6.3
通讯作者：
Katusic, Zvonimir S.
中科院分区：
文献类型：
--
作者：
He, Tongrong;Santhanam, Anantha Vijay R.;Katusic, Zvonimir S.
我们测试了以下假设：脑微血管中前列环素 (PGI(2)) 受体 (IP 受体) 信号通路的激活在淀粉样前体蛋白 (APP) 的代谢中发挥重要作用。在人脑微血管内皮细胞中，PGI(2) 的稳定类似物伊洛前列素激活 IP 受体，刺激淀粉样前体蛋白和解整合素和金属蛋白酶 10 (ADAM10) 的表达，导致神经保护和抗凝分子可溶性 APP α (sAPP α) 的产生增加。 IP 受体的选择性激动剂西卡前列素和腺苷酸环化酶激活剂毛喉素也能增强淀粉样前体蛋白和 ADAM10 的表达。值得注意的是，在 IP 受体敲除小鼠的脑微血管中，APP 和 ADAM10 的蛋白水平降低。此外，伊洛前列素还能增加人脑微血管内皮细胞中过氧化物酶体增殖物激活受体δ（PPAR δ）的蛋白质水平。 PPAR delta-siRNA 消除了伊洛前列素增强的 ADAM10 蛋白表达。相比之下，GW501516（PPAR δ 的选择性激动剂）上调 ADAM10 并增加 sAPP α 的产生。小鼠内皮 PPAR δ (ePPAR δ(-/-)) 的基因缺失显着降低了 ADAM10 的脑微血管表达和 sAPP α 的产生。 GW501516的体内治疗增加了野生型小鼠海马中的sAPP α含量，但不增加ePPAR delta(-/-)小鼠海马中的sAPP α含量。我们的研究结果发现了以前未被认识到的 IP-PPAR δ 信号转导途径在脑微血管系统 sAPP α 产生中的作用。
We tested hypothesis that activation of the prostacyclin (PGI(2)) receptor (IP receptor) signaling pathway in cerebral microvessels plays an important role in the metabolism of amyloid precursor protein (APP). In human brain microvascular endothelial cells activation of IP receptor with the stable analogue of PGI(2), iloprost, stimulated expression of amyloid precursor protein and a disintegrin and metalloprotease 10 (ADAM10), resulting in an increased production of the neuroprotective and anticoagulant molecule, soluble APP alpha (sAPP alpha). Selective agonist of IP receptor, cicaprost, and adenylyl cyclase activator, forskolin, also enhanced expression of amyloid precursor protein and ADAM10. Notably, in cerebral microvessels of IP receptor knockout mice, protein levels of APP and ADAM10 were reduced. In addition, iloprost increased protein levels of peroxisome proliferator-activated receptor delta (PPAR delta) in human brain microvascular endothelial cells. PPAR delta-siRNA abolished iloprost-augmented protein expression of ADAM10. In contrast, GW501516 (a selective agonist of PPAR delta) upregulated ADAM10 and increased production of sAPP alpha. Genetic deletion of endothelial PPAR delta (ePPAR delta(-/-)) in mice significantly reduced cerebral microvascular expression of ADAM10 and production of sAPP alpha. In vivo treatment with GW501516 increased sAPP alpha content in hippocampus of wild type mice but not in hippocampus of ePPAR delta(-/-) mice. Our findings identified previously unrecognized role of IP-PPAR delta signal transduction pathway in the production of sAPP alpha in cerebral microvasculature.