Paxillin suppresses the proliferation of HPS rat serum treated PASMCs by up-regulating the expression of cytoskeletal proteins
Paxillin suppresses the proliferation of HPS rat serum treated PASMCs by up-regulating the expression of cytoskeletal proteins
复制标题
Paxillin 通过上调细胞骨架蛋白的表达来抑制 HPS 大鼠血清处理的 PASMC 的增殖。
DOI：
10.1039/c3mb70391f
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发表时间：
2014-01-01
影响因子：
--
通讯作者：
Lu, Kaizhi
中科院分区：
文献类型：
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作者：
Chen, Yang;Yi, Bin;Lu, Kaizhi
肝肺综合征(HPS)是晚期肝病、肺内血管扩张(IPVD)和动脉低氧血症的三位一体。动脉低氧血症导致肺血管重构(PVR)。最近的研究表明，肺动脉平滑肌细胞(PASMCs)的增殖在HPS相关的PVR中的作用已得到证实，细胞骨架蛋白的变化在PASMCs的增殖中起着至关重要的作用。关于细胞骨架蛋白表达的相关性或PVR与HPS相关的分子机制还知之甚少。此外，研究还发现，在肺癌、肝癌等多种疾病中，巴西林通过一些重要的信号转导途径影响细胞骨架蛋白的表达。在本研究中，我们发现胆总管结扎模型大鼠血清降低了PASMCs细胞骨架蛋白(α-肌动蛋白、α-微管蛋白和降钙素)的表达，增强了PASMCs中PXILLIN基因和蛋白的表达水平。在用siRNA沉默paxlin后，我们发现HPS大鼠血清诱导的细胞骨架蛋白表达的下调被逆转。此外，我们还报道了HPS大鼠血清可促进PASMCs的增殖，而下调巴西林可显著抑制这一变化。这些结果提示，巴西林诱导的细胞骨架蛋白表达上调可能导致PASMC增殖失调，在HPS相关性PVR中起重要作用。综上所述，siRNA下调Paxlin的表达可抑制细胞骨架蛋白的异常表达，抑制PASMCs的增殖，提示siRNA对HPS相关性PVR有潜在的治疗作用。
Hepatopulmonary syndrome (HPS) is a triad of advanced liver disease, intrapulmonary vasodilatation (IPVD), and arterial hypoxemia. The arterial hypoxemia induces pulmonary vascular remodelling (PVR). In recent studies, the role of the proliferation of pulmonary artery smooth muscle cells (PASMCs) in PVR associated with HPS has been established; the changes in cytoskeletal proteins play an essential role in the proliferation of PASMCs. Little is known about the relevance of cytoskeletal protein expression or the molecular mechanisms of PVR associated with HPS. In addition, it has been identified that paxillin could influence the cytoskeletal protein expression by some important signaling pathways in many diseases, including lung cancer and liver cancer. In this study, we found that HPS rat serum from a common bile duct ligation (CBDL) rat model decreased the expression of cytoskeletal proteins (α-actin, α-tubulin, and destrin) and enhanced the expression levels of paxillin mRNA and protein in PASMCs. After silencing paxillin with siRNA, we found that the down-regulation of cytoskeletal protein expression, induced by the HPS rat serum, was reversed. Additionally, we reported that HPS rat serum improved the proliferation of PASMCs and down-regulation of paxillin could significantly inhibit this variation. These findings suggest that the up-regulation of cytoskeletal protein expression, induced by the paxillin, may cause the dysregulation of PASMC proliferation as well as play a fundamental role in PVR associated with HPS. In conclusion, down-regulation of paxillin by siRNA results in the inhibition of the dysregulation of cytoskeletal proteins and proliferation of PASMCs, suggesting a potential therapeutic effect on PVR associated with HPS.