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首页> 外文期刊>Molecular and Cellular Biology >FoxO4 Regulates Tumor Necrosis Factor Alpha-Directed Smooth Muscle Cell Migration by Activating Matrix Metalloproteinase 9 Gene Transcription
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FoxO4 Regulates Tumor Necrosis Factor Alpha-Directed Smooth Muscle Cell Migration by Activating Matrix Metalloproteinase 9 Gene Transcription

机译：FoxO4通过激活基质金属蛋白酶9基因转录调节肿瘤坏死因子阿尔法定向的平滑肌细胞迁移。

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摘要

Phenotypic modulation of vascular smooth muscle cells (SMCs) in the blood vessel wall from a differentiated to a proliferative state during vascular injury and inflammation plays an important role in restenosis and atherosclerosis. Matrix metalloproteinase 9 (MMP9) is a member of the MMP family of proteases, which participate in extracellular matrix degradation and turnover. MMP9 is upregulated and required for SMC migration during the development of restenotic and atherosclerotic lesions. In this study, we show that FoxO4 activates transcription of the MMP9 gene in response to tumor necrosis factor alpha (TNF-α) signaling. Inhibition of FoxO4 expression by small interfering RNA or gene knockout reduces the abilities of SMCs to migrate in vitro and inhibit neointimal formation and MMP9 expression in vivo. We further show that both the N-terminal, Sp1-interactive domain and the C-terminal transactivation domain of FoxO4 are required for FoxO4-activated MMP9 transcription. TNF-α signaling upregulates nuclear FoxO4. Our studies place FoxO4 in the center of a transcriptional regulatory network that links gene transcription required for SMC remodeling to upstream cytokine signals and implicate FoxO4 as a potential therapeutic target for combating proliferative arterial diseases.
机译：在血管损伤和炎症过程中，血管壁中血管平滑肌细胞（SMC）从分化状态到增殖状态的表型调节在再狭窄和动脉粥样硬化中起重要作用。基质金属蛋白酶9（MMP9）是蛋白酶MMP家族的成员，其参与细胞外基质降解和更新。在再狭窄和动脉粥样硬化病变的发展过程中，MMP9上调并且是SMC迁移所必需的。在这项研究中，我们表明FoxO4激活MMP9基因的转录，以响应肿瘤坏死因子α（TNF-α）信号传导。小干扰RNA或基因敲除抑制FoxO4表达会降低SMC在体外迁移并抑制体内新内膜形成和MMP9表达的能力。我们进一步表明，FoxO4激活的MMP9转录需要FoxO4的N末端，Sp1交互域和C末端反式激活域。 TNF-α信号上调核FoxO4。我们的研究将FoxO4置于转录调节网络的中心，该网络将SMC重构所需的基因转录与上游细胞因子信号联系起来，并暗示FoxO4作为对抗增生性动脉疾病的潜在治疗靶标。

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