Aquaporin 1-mediated changes in pulmonary arterial smooth muscle cell migration and proliferation involve β-catenin
Aquaporin 1-mediated changes in pulmonary arterial smooth muscle cell migration and proliferation involve β-catenin
复制标题
水通道蛋白 1 介导的肺动脉平滑肌细胞迁移和增殖变化涉及 β-连环蛋白。
DOI：
10.1152/ajplung.00247.2016
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发表时间：
2017-11-01
影响因子：
4.9
通讯作者：
Shimoda, Larissa A.
中科院分区：
文献类型：
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作者：
Yun, Xin;Jiang, Haiyang;Shimoda, Larissa A.
低氧可诱导肺血管平滑肌细胞(PASMCs)迁移和增殖，导致血管重塑，导致缺氧性肺动脉高压的发生。尽管水通道蛋白1(Aquaporin 1，AQP1)在PASMC生长和运动中起重要作用，但其调控机制尚不完全清楚。在肿瘤、肾脏和干细胞中，AQP1已被证明与β-连环蛋白相互作用，β-连环蛋白是一种双功能蛋白，可激活与细胞迁移和增殖相关的关键靶基因(即c-Myc和细胞周期蛋白D1)的转录。因此，本研究的目的是研究AQP1介导PASMC迁移和增殖的机制，重点是β-连环蛋白。用含有绿色荧光蛋白(对照；AdGFP)、野生型AQP1(AdAQP1)或COOH末端缺失的AQP1(AdAQP1M)的腺病毒载体感染阻力水平的原代大鼠肺动脉平滑肌细胞，我们证明AQP1表达增加会上调β-catenin蛋白水平和已知的β-catenin靶标c-Myc和Cyclin D1的表达(mRNA和蛋白)。相比之下，感染AdAQP1M对这些变量中的任何一个都没有影响。使用沉默方法来降低β-连环素水平，可以阻止缺氧和AQP1诱导的PASMCs的迁移和增殖，以及AQP1诱导的c-Myc和细胞周期蛋白D1的表达。因此，我们的结果表明，AQP1水平的升高通过一种需要AQP1 COOH末端尾巴的机制上调β-连环蛋白的蛋白水平，增强β-连环蛋白靶标的表达，并促进PASMC的增殖和迁移。
Exposure to hypoxia induces migration and proliferation of pulmonary arterial smooth muscle cells (PASMCs), leading to vascular remodeling and contributing to the development of hypoxic pulmonary hypertension. The mechanisms controlling PASMC growth and motility are incompletely understood, although aquaporin 1 (AQP1) plays an important role. In tumor, kidney, and stem cells, AQP1 has been shown to interact with beta-catenin, a dual function protein that activates the transcription of crucial target genes (i.e., c-Myc and cyclin D1) related to cell migration and proliferation. Thus the goal of this study was to examine mechanisms by which AQP1 mediates PASMC migration and proliferation, with a focus on beta-catenin. Using primary rat PASMCs from resistance level pulmonary arteries infected with adenoviral constructs containing green fluorescent protein (control; AdGFP), wild-type AQP1 (AdAQP1), or AQP1 with the COOHterminal tail deleted (AdAQP1M), we demonstrated that increasing AQP1 expression upregulated beta-catenin protein levels and the expression (mRNA and protein) of the known beta-catenin targets c-Myc and cyclin D1. In contrast, infection with AdAQP1M had no effect on any of these variables. Using silencing approaches to reduce beta-catenin levels prevented both hypoxia-and AQP1-induced migration and proliferation of PASMCs, as well as induction of c-Myc and cyclin D1 by AQP1. Thus our results indicate that elevated AQP1 levels upregulate beta-catenin protein levels, via a mechanism requiring the AQP1 COOH-terminal tail, enhancing expression of beta-catenin targets and promoting PASMC proliferation and migration.