Inhibition of CXCL12/CXCR4 suppresses pulmonary arterial smooth muscle cell proliferation and cell cycle progression via PI3K/Akt pathway under hypoxia
Inhibition of CXCL12/CXCR4 suppresses pulmonary arterial smooth muscle cell proliferation and cell cycle progression via PI3K/Akt pathway under hypoxia
复制标题
缺氧条件下抑制 CXCL12/CXCR4 通过 PI3K/Akt 通路抑制肺动脉平滑肌细胞增殖和细胞周期进程
DOI：
10.3109/10799893.2014.984308
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发表时间：
2015-07-04
影响因子：
2.8
通讯作者：
Zhu, Daling
中科院分区：
文献类型：
--
作者：
Wei, Liuping;Zhang, Bo;Zhu, Daling
基质细胞衍生因子1（CXCL 12）及其受体CXC趋化因子受体4（CXCR 4）已知通过动员和募集祖细胞到肺血管来调节缺氧诱导的肺动脉高压（PH）和血管重构。然而，关于CXCL 12/CXCR 4调节肺动脉平滑肌细胞（PASMCs）增殖和细胞周期进展的研究知之甚少。本研究采用免疫组化、Western blot、溴脱氧尿苷掺入和细胞周期分析等方法，探讨CXCL 12/CXCR 4对PASMC增殖和细胞周期的调控作用。结果表明，低氧可诱导大鼠肺动脉和PASMCs产生CXCR 4。缺氧增加的细胞活力，DNA合成和增殖细胞核抗原表达被CXCR 4拮抗剂AMD 3100，沉默CXCR 4或CXCL 12的管理。此外，抑制CXCL 12/CXCR 4抑制细胞周期进程，减少S+G2/M期细胞的数量，并减弱在这些阶段调节细胞周期进程的蛋白质的表达。此外，PI 3 K/Akt信号通路介导CXCL 12/CXCR 4调节PASMCs的增殖和细胞周期进程。因此，这些结果表明，阻断CXCL 12/CXCR 4通过PI 3 K/Akt信号通路抑制低氧诱导的PH中的PASMC增殖和细胞周期进展。
Stromal cell-derived factor 1 (CXCL12) and its receptor CXC chemokine receptor 4 (CXCR4) are known to modulate hypoxia-induced pulmonary hypertension (PH) and vascular remodeling by mobilization and recruitment of progenitor cells to the pulmonary vasculature. However, little is known about CXCL12/CXCR4 regulating proliferation and cell cycle progression of pulmonary arterial smooth muscle cells (PASMCs). To determine whether CXCL12/CXCR4 regulates PASMC proliferation and the cell cycle, immunohistochemistry, Western blot, bromodeoxyuridine incorporation and cell cycle analysis were preformed in this study. Our results showed that CXCR4 was induced by hypoxia in pulmonary arteries and PASMCs of rats. Hypoxia-increased cell viability, DNA synthesis and proliferating cell nuclear antigen expression were blocked by administration of CXCR4 antagonist AMD3100, silencing CXCR4 or CXCL12. Furthermore, inhibition of CXCL12/CXCR4 suppressed cell cycle progression, decreased the number of cells in S+G2/M phase and attenuated the expression of proteins that regulate the cell cycle progression at these phases. In addition, PI3K/Akt signaling mediated CXCL12/CXCR4 regulating proliferation and cell cycle progression in PASMCs. Thus, these results indicate that blockade of CXCL12/CXCR4 inhibited PASMC proliferation and cell cycle progression in hypoxia-induced PH via PI3K/Akt signaling pathway.