Regulation of S100A4 expression via the JAK2-STAT3 pathway in rhomboid-phenotype pulmonary arterial smooth muscle cells exposure to hypoxia
Regulation of S100A4 expression via the JAK2-STAT3 pathway in rhomboid-phenotype pulmonary arterial smooth muscle cells exposure to hypoxia
复制标题
缺氧条件下菱形表型肺动脉平滑肌细胞通过 JAK2-STAT3 通路调节 S100A4 表达
DOI：
10.1016/j.biocel.2012.04.017
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发表时间：
2012-08-01
影响因子：
4
通讯作者：
Wang, Guansong
中科院分区：
文献类型：
--
作者：
Liu, Ting;Li, Yuncheng;Wang, Guansong
为探讨JAKs-STATS信号通路对肺动脉平滑肌细胞(PASMCs)S100A4表达的影响，以及S100A4和缺氧诱导因子1(HIF-1)对缺氧PASMC增殖的影响。结果表明，S100A4免疫染色定位于缺氧PASMCs的胞浆和胞核，主要表达于菱形细胞(R-SMC)。低氧刺激4、8、16h后，PASMCs S100A4mRNA和蛋白表达水平升高，经HIF-1αsiRNA、STAT3siRNA、S100A4siRNA和S100A4抑制剂NSC 95397预处理后，S100A4的免疫荧光强度和蛋白水平受到抑制，R-SMC数量减少。经HIF-1αsiRNA和抗IL-6抗体处理后，缺氧细胞中磷酸化JAK2、-STAT3和S100A4水平降低，而HIF-1α水平保持稳定。重要的是，HIF-1αsiRNA、抗IL-6抗体、STAT3 siRNA和S100A4 siRNA可显著抑制低氧暴露下PASMCs的增殖。这些结果表明，S100A4主要在缺氧的R-SMC中表达，并受JAK2-STAT3信号通路的激活调节，该信号通路依赖于缺氧诱导的HIF-1α的表达。提示JAK2-STAT3和HIF-1α可作为肺血管病变过程中PASMCs表型调控的靶点。(C)2012爱思唯尔有限公司。保留所有权利。
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-1 alpha siRNA, STAT3 siRNA, S100A4 siRNA, and S100A4 inhibitor NSC 95397. Pretreatment with HIF-1 alpha siRNA and anti-IL-6 antibodies, the levels of phospho-JAK2, -STAT3, and S100A4 were decreased, while HIF-1 alpha kept stable in hypoxic cells. Importantly, pretreatment with HIF-1 alpha 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-1 alpha expression. These results suggest that JAK2-STAT3 and HIF-1 alpha could serve as targets for the regulation of phenotype modulation of PASMCs during the process of pulmonary vessel lesions. (C) 2012 Elsevier Ltd. All rights reserved.