Mnk1 is required for angiotensin II - Induced protein synthesis in vascular smooth muscle cells
Mnk1 is required for angiotensin II - Induced protein synthesis in vascular smooth muscle cells
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DOI：
10.1161/01.res.0000105570.34585.f2
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发表时间：
2003-12-12
影响因子：
20.1
通讯作者：
Yoshizumi, M
中科院分区：
文献类型：
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作者：
Ishida, M;Ishida, T;Yoshizumi, M
血管紧张素 II (Ang II) 刺激血管平滑肌细胞 (VSMC) 中的蛋白质合成，可能继发于 mRNA 翻译起始时的调节变化。丝裂原激活蛋白 (MAP) 激酶信号 - 整合激酶 1 (Mnk1)（ERK 和 p38 MAP 激酶的底物）磷酸化真核起始因子 4E (eIF4E)，这是翻译中的重要因子。本研究的目的是研究 Mnk1 在 Ang II 诱导的蛋白质合成中的作用，并表征 Mnk1 和 eIF4E 在大鼠 VSMC 中激活的分子机制。 Ang II 处理导致 Mnk1 活性和 eIF4E 磷酸化增加。显性失活 Mnk1 突变体的表达消除了 Ang II 诱导的 eIF4E 磷酸化。 PD98059或引入激酶失活的MEK1/MKK1，但不是SB202190或激酶失活的p38 MAP激酶，抑制Ang II诱导的Mnk1激活和eIF4E磷酸化，表明Ang II诱导的Mnk1-eIF4E激活需要ERK，而不是p38 MAP激酶。此外，Ras（而非 Rho、Rac 或 Cdc42）的显性失活构建体消除了 Ang II 诱导的 Mnk1 激活。最后，用 CGP57380（一种新型的 Mnk1 特异性激酶抑制剂）治疗 VSMC，导致 Ang II 刺激的 eIF4E 磷酸化、蛋白质合成和 VSMC 肥大出现剂量依赖性下降。总之，这些数据表明（1）Ang II 诱导的 Mnk1 激活是由 VSMC 中的 Ras-ERK 级联介导的，（2）Mnk1 参与 Ang II 介导的蛋白质合成和肥大，可能是通过翻译起始的激活。 Mnk1-eIF4E 通路可能为血管肥大和其他 Ang II 介导的病理状态的分子机制提供新的见解。
Angiotensin II (Ang II) stimulates protein synthesis in vascular smooth muscle cells (VSMCs), possibly secondary to regulatory changes at the initiation of mRNA translation. Mitogen-activated protein ( MAP) kinase signal - integrating kinase-1 (Mnk1), a substrate of ERK and p38 MAP kinase, phosphorylates eukaryotic initiation factor 4E (eIF4E), an important factor in translation. The goal of the present study was to investigate the role of Mnk1 in Ang II - induced protein synthesis and to characterize the molecular mechanisms by which Mnk1 and eIF4E is activated in rat VSMCs. Ang II treatment resulted in increased Mnk1 activity and eIF4E phosphorylation. Expression of a dominant-negative Mnk1 mutant abolished Ang II - induced eIF4E phosphorylation. PD98059 or introduction of kinase-inactive MEK1/MKK1, but not SB202190 or kinase-inactive p38 MAP kinase, inhibited Ang II - induced Mnk1 activation and eIF4E phosphorylation, suggesting that ERK, but not p38 MAP kinase, is required for Ang II - induced Mnk1-eIF4E activation. Further, dominant-negative constructs for Ras, but not for Rho, Rac, or Cdc42, abolished Ang II - induced Mnk1 activation. Finally, treatment of VSMCs with CGP57380, a novel specific kinase inhibitor of Mnk1, resulted in dose-dependent decreases in Ang II - stimulated phosphorylation of eIF4E, protein synthesis, and VSMC hypertrophy. In summary, these data demonstrated that ( 1) Ang II - induced Mnk1 activation is mediated by the Ras-ERK cascade in VSMCs, and ( 2) Mnk1 is involved in Ang II - mediated protein synthesis and hypertrophy, presumably through the activation of translation-initiation. The Mnk1-eIF4E pathway may provide new insights into molecular mechanisms involved in vascular hypertrophy and other Ang II - mediated pathological states.