Macrophage EP4 deficiency increases apoptosis and suppresses early atherosclerosis.
Macrophage EP4 deficiency increases apoptosis and suppresses early atherosclerosis.
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DOI：
10.1016/j.cmet.2008.09.005
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发表时间：
2008-12
期刊：
影响因子：
29
通讯作者：
Linton, MacRae F.
中科院分区：
文献类型：
--
作者：
Babaev, Vladimir R.;Chew, Joshua D.;Ding, Lei;Davis, Sarah;Breyer, Matthew D.;Breyer, Richard M.;Oates, John A.;Fazio, Sergio;Linton, MacRae F.
前列腺素（PG）E2是活化的巨噬细胞的主要产物，与动脉粥样硬化和斑块破裂有关。PGE 2受体EP 2和EP 4在动脉粥样硬化病变中表达，并且已知其抑制癌细胞的凋亡。为了研究巨噬细胞EP 4和EP 2在细胞凋亡和早期动脉粥样硬化中的作用，使用胎肝细胞移植来产生EP 2 −/−或EP 4 −/−造血细胞嵌合的LDLR−/−小鼠。在西方饮食8周后，EP 4 −/− → LDLR−/−小鼠（而非EP 2 −/− → LDLR−/−小鼠）的主动脉粥样硬化显著减少，病变中的凋亡细胞增加。EP 4 −/−腹腔巨噬细胞对促凋亡刺激的敏感性增加，包括棕榈酸和游离胆固醇负荷，这伴随着p-Akt，p-Bad和NF-κ B调节基因的活性抑制。因此，EP 4缺陷抑制PI 3 K/Akt和NF-κ B途径，损害巨噬细胞存活并抑制早期动脉粥样硬化，鉴定巨噬细胞EP 4信号传导途径为调节动脉粥样硬化发展的分子靶标。
Prostagladin (PG) E2, a major product of activated macrophages, has been implicated in atherosclerosis and plaque rupture. The PGE2 receptors, EP2 and EP4, are expressed in atherosclerotic lesions and are known to inhibit apoptosis in cancer cells. To examine the roles of macrophage EP4 and EP2 in apoptosis and early atherosclerosis, fetal liver cell transplantation was used to generate LDLR−/− mice chimeric for EP2−/− or EP4−/− hematopoietic cells. After 8-weeks on a Western diet, EP4−/− → LDLR−/− mice, but not EP2−/− → LDLR−/− mice, had significantly reduced aortic atherosclerosis with increased apoptotic cells in the lesions. EP4−/− peritoneal macrophages had increased sensitivity to pro-apoptotic stimuli, including palmitic acid and free cholesterol loading, which was accompanied by suppression of activity of p-Akt, p-Bad and NF-kB-regulated genes. Thus, EP4 deficiency inhibits the PI3K/Akt and NF-kB pathways compromising macrophage survival and suppressing early atherosclerosis, identifying macrophage EP4 signaling pathways as molecular targets for modulating the development of atherosclerosis.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
DOI：
10.1073/pnas.0702663104
发表时间：
2007-05-08
影响因子：
11.1
作者：
Chang, James D.;Sukhova, Galina K.;Cantley, Lewis C.
通讯作者：
Cantley, Lewis C.
影响因子：
4.8
作者：
Fujino, H;Xu, W;Regan, JW
通讯作者：
Regan, JW
DOI：
10.1016/j.prostaglandins.2006.10.005
发表时间：
2007-02-01
影响因子：
2.9
作者：
George, Robert J.;Sturmoski, Mark A.;Houchen, Courtney W.
通讯作者：
Houchen, Courtney W.
DOI：
10.1073/pnas.94.9.4647
发表时间：
1997-04-29
影响因子：
11.1
作者：
Fazio, S;Babaev, VR;Linton, MF
通讯作者：
Linton, MF