Inhibition of EP4 signaling attenuates aortic aneurysm formation.
Inhibition of EP4 signaling attenuates aortic aneurysm formation.
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DOI：
10.1371/journal.pone.0036724
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Ishikawa Y
中科院分区：
文献类型：
--
作者：
Yokoyama U;Ishiwata R;Jin MH;Kato Y;Suzuki O;Jin H;Ichikawa Y;Kumagaya S;Katayama Y;Fujita T;Okumura S;Sato M;Sugimoto Y;Aoki H;Suzuki S;Masuda M;Minamisawa S;Ishikawa Y
主动脉瘤是老年人常见但危及生命的疾病，目前尚无有效的药物治疗方法。已知前列腺素 E2 (PGE2) 的激活会增加基质金属蛋白酶 (MMP) 的表达和炎性细胞因子的释放，从而可能加剧腹主动脉瘤 (AAA) 的形成。我们假设选择性阻断 PGE2，特别是 EP4 前列腺素受体信号传导，将减弱 AAA 的发展。人类 AAA 组织的免疫组织化学分析表明 EP4 在 AAA 区域的表达高于非患病区域。有趣的是，EP4表达与弹性纤维降解程度成正比。在培养的人主动脉平滑肌细胞（ASMC）中，PGE2刺激增加了EP4蛋白表达（1.4±0.08倍），而ONO-AE1-329刺激EP4增加了MMP-2活性和白细胞介素6（IL-6）产量（分别为1.4±0.03和1.7±0.14倍，P<0.05）。因此，我们在输注血管紧张素 II 的 AAA ApoE−/− 小鼠模型中检查了 EP4 抑制的效果。口服EP4拮抗剂ONO-AE3-208（0.01-0.5 mg/kg/天）4周可显着减少AAA的形成（减少45-87%，P<0.05）。类似地，EP4+/-/ApoE-/- 小鼠表现出比 EP4+/+/ApoE-/- 小鼠显着更少的 AAA 形成（减少 76%，P<0.01）。与野生型小鼠相比，EP4+/- 小鼠主动脉周围 CaCl2 应用诱导的 AAA 形成也减少（减少 73%，P<0.001）。此外，在含有 SMC 和巨噬细胞的人 AAA 组织器官培养物中，10-100 nM 剂量的 EP4 拮抗剂可降低 MMP-2 活化和 IL-6 产生（分别为 0.6±0.06 和 0.7±0.06 倍，P<0.05），而不增加 MMP-9 活性或 MCP-1 分泌。因此，在多种小鼠和人类模型中，药理学或遗传性的 EP4 抑制通过降低 MMP 活性和细胞因子释放来减弱 AAA 的形成。 EP4拮抗剂可以阻止MMP的激活，从而抑制主动脉弹力纤维的降解，可能成为治疗AAA的新策略。
Aortic aneurysm is a common but life-threatening disease among the elderly, for which no effective medical therapy is currently available. Activation of prostaglandin E2 (PGE2) is known to increase the expression of matrix metalloproteinase (MMP) and the release of inflammatory cytokines, and may thus exacerbate abdominal aortic aneurism (AAA) formation. We hypothesized that selective blocking of PGE2, in particular, EP4 prostanoid receptor signaling, would attenuate the development of AAA. Immunohistochemical analysis of human AAA tissues demonstrated that EP4 expression was greater in AAA areas than that in non-diseased areas. Interestingly, EP4 expression was proportional to the degree of elastic fiber degradation. In cultured human aortic smooth muscle cells (ASMCs), PGE2 stimulation increased EP4 protein expression (1.4±0.08-fold), and EP4 stimulation with ONO-AE1-329 increased MMP-2 activity and interleukin-6 (IL-6) production (1.4±0.03- and 1.7±0.14-fold, respectively, P<0.05). Accordingly, we examined the effect of EP4 inhibition in an ApoE−/− mouse model of AAA infused with angiotensin II. Oral administration of ONO-AE3-208 (0.01–0.5 mg/kg/day), an EP4 antagonist, for 4 weeks significantly decreased the formation of AAA (45–87% reduction, P<0.05). Similarly, EP4+/−/ApoE−/− mice exhibited significantly less AAA formation than EP4+/+/ApoE−/− mice (76% reduction, P<0.01). AAA formation induced by periaortic CaCl2 application was also reduced in EP4+/− mice compared with wild-type mice (73% reduction, P<0.001). Furthermore, in human AAA tissue organ cultures containing SMCs and macrophages, doses of the EP4 antagonist at 10–100 nM decreased MMP-2 activation and IL-6 production (0.6±0.06- and 0.7±0.06-fold, respectively, P<0.05) without increasing MMP-9 activity or MCP-1 secretion. Thus, either pharmacological or genetic EP4 inhibition attenuated AAA formation in multiple mouse and human models by lowering MMP activity and cytokine release. An EP4 antagonist that prevents the activation of MMP and thereby inhibits the degradation of aortic elastic fiber may serve as a new strategy for medical treatment of AAA.
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影响因子：
10.8
作者：
Hishikari, Keiichi;Suzuki, Jun-ichi;Isobe, Mitsuaki
通讯作者：
Isobe, Mitsuaki
影响因子：
15.9
作者：
Longo, GM;Xiong, WF;Baxter, BT
通讯作者：
Baxter, BT
DOI：
10.1161/atvbaha.110.216580
发表时间：
2011-02
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Tang EH;Shvartz E;Shimizu K;Rocha VZ;Zheng C;Fukuda D;Shi GP;Sukhova G;Libby P
通讯作者：
Libby P
影响因子：
15.9
作者：
Nataraj, C;Thomas, DW;Coffman, TM
通讯作者：
Coffman, TM
DOI：
10.1161/01.atv.0000177814.41505.41
发表时间：
2005-09-01
影响因子：
8.7
作者：
Cipollone, F;Fazia, ML;Mezzetti, A
通讯作者：
Mezzetti, A