The Prostaglandin E2 Receptor EP4 Promotes Vascular Neointimal Hyperplasia through Translational Control of Tenascin C via the cAPM/PKA/mTORC1/rpS6 Pathway.
The Prostaglandin E2 Receptor EP4 Promotes Vascular Neointimal Hyperplasia through Translational Control of Tenascin C via the cAPM/PKA/mTORC1/rpS6 Pathway.
复制标题
前列腺素 E2 受体 EP4 通过 cAMP/PKA/mTORC1/rpS6 途径翻译控制腱蛋白 C，促进血管新内膜增生
作者：
前列腺素E2 （Prostaglandin E2, PGE2）是花生四烯酸的重要代谢物，通过其四种受体在血管生理和病理生理中起重要作用（EP1-4）。然而，血管平滑肌细胞（VSMC） EP4在新生内膜增生中的作用在很大程度上是未知的。我们发现，在股动脉丝损伤或颈动脉结扎小鼠中，vsmc特异性的EP4缺失（VSMC-EP4）得到改善，而vsmc特异性的人EP4过表达促进了新生内膜增生。体外研究表明，EP4的药理激活促进了原代培养VSMCs的增殖和迁移，而抑制EP4则抑制了VSMCs的增殖和迁移。机械上，EP4在翻译水平上显著增加tenascin C （TN-C）的蛋白表达，tenascin C是一种促增殖和促迁移的细胞外基质蛋白。敲低TN-C可显著抑制EP4激动剂诱导的VSMC增殖和迁移。进一步的研究发现，EP4通过PKA/mTORC1/核糖体蛋白S6 （rpS6）途径上调TN-C蛋白的表达。总之，我们的研究结果表明，VSMC EP4通过PKA-mTORC1-rpS6途径增加TN-C蛋白表达，促进内膜增生。因此，VSMC EP4可能是血管再狭窄的潜在治疗靶点。
Prostaglandin E2 (PGE2) is an important metabolite of arachidonic acid which plays a crucial role in vascular physiology and pathophysiology via its four receptors (EP1-4). However, the role of vascular smooth muscle cell (VSMC) EP4 in neointimal hyperplasia is largely unknown. Here we showed that VSMC-specific deletion of EP4 (VSMC-EP4) ameliorated, while VSMC-specific overexpression of human EP4 promoted, neointimal hyperplasia in mice subjected to femoral artery wire injury or carotid artery ligation. In vitro studies revealed that pharmacological activation of EP4 promoted, whereas inhibition of EP4 suppressed, proliferation and migration of primary-cultured VSMCs. Mechanically, EP4 significantly increased the protein expression of tenascin C (TN-C), a pro-proliferative and pro-migratory extracellular matrix protein, at the translational level. Knockdown of TN-C markedly suppressed EP4 agonist-induced VSMC proliferation and migration. Further studies uncovered that EP4 upregulated TN-C protein expression via the PKA/mTORC1/Ribosomal protein S6 (rpS6) pathway. Together, our findings demonstrate that VSMC EP4 increases TN-C protein expression to promote neointimal hyperplasia via the PKA-mTORC1-rpS6 pathway. Therefore, VSMC EP4 may represent a potential therapeutic target for vascular restenosis.
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影响因子：
4.8
作者：
Rao, Reena;Redha, Reyadh;Pozzi, Ambra
通讯作者：
Pozzi, Ambra
DOI：
10.1083/jcb.201102090
发表时间：
2011-09-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Liu L;Parent CA
通讯作者：
Parent CA
影响因子：
--
作者：
Habib, Anwer;Finn, Aloke Virmani
通讯作者：
Finn, Aloke Virmani
影响因子：
39.3
作者：
Kang, Hyun-Jae;Oh, Il-Young;Kim, Hyo-Soo
通讯作者：
Kim, Hyo-Soo
影响因子：
5.6
作者：
Moore, Claire E. J.;Xie, Jianling;Herbert, Terence P.
通讯作者：
Herbert, Terence P.