EPA Prevents the Development of Abdominal Aortic Aneurysms through Gpr-120/Ffar-4.
EPA Prevents the Development of Abdominal Aortic Aneurysms through Gpr-120/Ffar-4.
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DOI：
10.1371/journal.pone.0165132
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Yoshizumi M
中科院分区：
文献类型：
--
作者：
Kamata R;Bumdelger B;Kokubo H;Fujii M;Yoshimura K;Ishida T;Ishida M;Yoshizumi M
腹主动脉瘤（AAA）常见于老年人，伴有破裂风险和高死亡率。尽管据报道二十碳五烯酸 (EPA) 可以防止 AAA 形成，但 EPA 对血管平滑肌细胞的作用机制尚不清楚。本研究旨在探讨口服 EPA 预防骨保护素 (Opg) 敲除 (KO) 小鼠严重 AAA 形成的机制。在 CaCl2 诱导的 AAA 模型中，EPA 减弱了 Opg-KO 小鼠 AAA 的增强进展，包括主动脉直径的增加和中层弹性纤维的破坏。免疫组织化学分析表明，EPA 降低了主动脉中层转化生长因子 β 激活激酶 1/Map3k7 (Tak-1) 和 c-Jun NH2 末端激酶 (JNK) 的磷酸化，以及基质金属蛋白酶 9 (Mmp-9) 的表达。在平滑肌细胞培养物中，rh-TRAIL 诱导的 Tak-1-JNK 通路激活和 Mmp-9 表达增加被 EPA 抑制。此外，GW9508是G蛋白偶联受体(Gpr)-120/游离脂肪酸受体(Ffar)-4的特异性配体，模仿了EPA的作用。 EPA 的作用可通过敲低 Gpr-120/Ffar-4 受体基因而消除。我们的数据表明，Trail-Tak-1-JNK-Mmp-9 通路负责 Opg-KO 小鼠中 AAA 的增强，并且 EPA 通过激活 Gpr-120/Ffar-4 抑制 Tak-1-JNK 通路，从而导致 AAA 发育减弱。
Abdominal aortic aneurysms (AAAs), which commonly occur among elderly individuals, are accompanied by a risk of rupture with a high mortality rate. Although eicosapentaenoic acid (EPA) has been reported to prevent AAA formation, the mechanism by which EPA works on vascular smooth muscle cells is unknown. This study aimed to investigate the mechanism by which orally-administered EPA prevents the formation of severe AAAs that develop in Osteoprotegerin (Opg) knockout (KO) mice. In the CaCl2-induced AAA model, EPA attenuated the enhanced progression of AAAs in Opg-KO mice, including the increase in aortic diameter with destruction of elastic fibers in the media. Immunohistochemical analyses showed that EPA reduced the phosphorylation of transforming growth factor beta-activated kinase-1/Map3k7 (Tak-1) and c-Jun NH2-terminal kinase (JNK), as well as the expression of Matrix metalloproteinase-9 (Mmp-9) in the media of the aorta. In smooth muscle cell cultures, rh-TRAIL-induced activation of the Tak-1-JNK pathway and increase in Mmp-9 expression were inhibited by EPA. Moreover, GW9508, a specific ligand for G-protein coupled receptor (Gpr)-120/Free fatty acid receptor (Ffar)-4, mimicked the effects of EPA. The effects of EPA were abrogated by knockdown of the Gpr-120/Ffar-4 receptor gene. Our data demonstrate that the Trail-Tak-1-JNK-Mmp-9 pathway is responsible for the enhancement of AAAs in Opg-KO mice, and that EPA inhibits the Tak-1-JNK pathway by activating Gpr-120/Ffar-4, which results in the attenuation of AAA development.
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影响因子：
3.7
作者：
Bumdelger B;Kokubo H;Kamata R;Fujii M;Yoshimura K;Aoki H;Orita Y;Ishida T;Ohtaki M;Nagao M;Ishida M;Yoshizumi M
通讯作者：
Yoshizumi M
影响因子：
82.9
作者：
Yoshimura, K;Aoki, H;Matsuzaki, M
通讯作者：
Matsuzaki, M
影响因子：
15.9
作者：
Longo, GM;Xiong, WF;Baxter, BT
通讯作者：
Baxter, BT
DOI：
10.1161/atvbaha.107.147868
发表时间：
2007-09-01
影响因子：
8.7
作者：
Orita, Yuichi;Yamamoto, Hideya;Yoshizumi, Masao
通讯作者：
Yoshizumi, Masao
DOI：
10.1161/01.atv.0000236428.91125.e6
发表时间：
2006-09-01
影响因子：
8.7
作者：
Bennett, Brian J.;Scatena, Marta;Rosenfeld, Michael E.
通讯作者：
Rosenfeld, Michael E.