Institute of Respiratory Diseases, the Second Affiliated Hospital of the Third Military Medical University, Chongqing 400037, PR China.
Int J Biochem Cell Biol. 2012 Aug;44(8):1337-45. doi: 10.1016/j.biocel.2012.04.017. Epub 2012 Apr 27.
To investigate the effect of JAKs-STATs signal pathway on expression of S100A4 in pulmonary arterial smooth muscle cells (PASMCs), the action of S100A4 and hypoxia induced factor 1 (HIF-1) on the proliferation of hypoxic PASMCs. The results showed that S100A4 immunostaining was localized in the cytoplasm and nuclei of PASMCs exposure to hypoxia and it was predominantly expressed in rhomboid cells (R-SMCs). The mRNA and protein levels of S100A4 expression increased in PASMCs after hypoxic stimulus for 4, 8, 16 h. The immunofluorescence intensity and protein levels of S100A4 were suppressed, and the number of R-SMCs was reduced, when pretreatment with HIF-1α siRNA, STAT3 siRNA, S100A4 siRNA, and S100A4 inhibitor NSC 95397. Pretreatment with HIF-1α siRNA and anti-IL-6 antibodies, the levels of phospho-JAK2, -STAT3, and S100A4 were decreased, while HIF-1α kept stable in hypoxic cells. Importantly, pretreatment with HIF-1α siRNA, anti-IL-6 antibodies, STAT3 siRNA, and S100A4 siRNA, significantly attenuated the proliferation of PASMCs exposure to hypoxia. These data demonstrate that S100A4 is predominantly expressed in hypoxic R-SMCs, and regulated by the activation of JAK2-STAT3 signal pathway, which is dependent on hypoxia-induced HIF-1α expression. These results suggest that JAK2-STAT3 and HIF-1α could serve as targets for the regulation of phenotype modulation of PASMCs during the process of pulmonary vessel lesions.
为了研究 JAKs-STATs 信号通路对肺动脉平滑肌细胞（PASMCs）中 S100A4 表达的影响，以及 S100A4 和低氧诱导因子 1（HIF-1）对低氧 PASMCs 增殖的作用。结果表明，S100A4 免疫染色定位于暴露于低氧的 PASMCs 的细胞质和细胞核中，主要表达于菱形细胞（R-SMCs）。低氧刺激 4、8、16 h 后，PASMCs 中 S100A4 的 mRNA 和蛋白水平表达增加。用 HIF-1α siRNA、STAT3 siRNA、S100A4 siRNA 和 S100A4 抑制剂 NSC 95397 预处理后，S100A4 的免疫荧光强度和蛋白水平降低，R-SMCs 的数量减少。用 HIF-1α siRNA 和抗 IL-6 抗体预处理后，磷酸化 JAK2、STAT3 和 S100A4 的水平降低，而低氧细胞中的 HIF-1α 保持稳定。重要的是，用 HIF-1α siRNA、抗 IL-6 抗体、STAT3 siRNA 和 S100A4 siRNA 预处理，显著抑制了低氧 PASMCs 的增殖。这些数据表明，S100A4 主要表达于低氧 R-SMCs，受 JAK2-STAT3 信号通路的激活调节，该通路依赖于低氧诱导的 HIF-1α 表达。这些结果表明，JAK2-STAT3 和 HIF-1α 可作为调节肺动脉平滑肌细胞表型改变的靶点，参与肺血管病变过程。
