Inhibition of ubiquitin proteasome function suppresses proliferation of pulmonary artery smooth muscle cells
Inhibition of ubiquitin proteasome function suppresses proliferation of pulmonary artery smooth muscle cells
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DOI：
10.1007/s00210-011-0678-y
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发表时间：
2011-08
期刊：
影响因子：
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通讯作者：
Manxiang Li;Xi-lin Dong;Yuan Liu;Xiu-zhen Sun;Zongfang Li;Jiyin He
中科院分区：
文献类型：
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作者：
Manxiang Li;Xi-lin Dong;Yuan Liu;Xiu-zhen Sun;Zongfang Li;Jiyin He
抑制蛋白酶体功能已被证明可以抑制多种类型的细胞增殖;本研究探讨这种情况是否也发生在肺动脉平滑肌细胞（PASMC）中及其潜在机制。5-羟色胺诱导PASMCs的DNA合成增加4.27倍，并且这种作用被预先与特异性蛋白酶体抑制剂MG 132孵育的细胞剂量依赖性地阻断。蛋白酶体功能的抑制并不调节降钙素触发的促增殖信号通路，如细胞外信号调节的促分裂原活化蛋白激酶（ERK 1/2 MAPK）和Ras同源基因家族成员A（RhoA）。进一步研究表明，5-羟色胺处理PASMCs可降低p21 WAF 1蛋白水平，但不影响其转录，抑制ERK 1/2 MAPK或RhoA级联反应可逆转p21 WAF 1蛋白水平的降低。此外，在5-羟色胺存在下，MG 132以剂量依赖方式增加p21 WAF 1蛋白水平，10 μM MG 132导致p21 WAF 1蛋白水平增加4.2倍，并且这种作用不是通过增加p21 WAF 1 mRNA水平介导的。更重要的是，通过siRNA转染缺失p21 WAF 1的细胞，可以消除MG 132对细胞增殖的抑制作用。提示抑制蛋白酶体引起的p21 WAF 1蛋白水平升高是其抑制PASMCs增殖的重要机制，抑制蛋白酶体功能可能对肺动脉高压的治疗具有潜在价值。
Inhibition of proteasome function has been shown to suppress several types of cells proliferation; this study investigates whether this also occurs in pulmonary artery smooth muscle cells (PASMCs) and its potential mechanisms. Serotonin induced 4.27-fold increase in DNA synthesis in PASMCs, and this effect was dose-dependently blocked by prior incubation of cells with MG132, a specific proteasome inhibitor. Inhibition of proteasome function did not modulate serotonin-triggered pro-proliferation signaling pathways, such as extracellular signal-regulated mitogen-activated protein kinase (ERK1/2 MAPK) and Ras homolog gene family member A (RhoA). Further study indicated that treatment of PASMCs with serotonin reduced p21WAF1protein level but not its transcription; this was reversed by inhibiting ERK1/2 MAPK or RhoA cascade equally. In addition, MG132 increased the protein level of p21WAF1in a dose-dependent manner in the presence of serotonin, 10 μM MG132 led to a 4.2-fold increase in p21WAF1protein level, and this effect was not mediated by increasing p21WAF1mRNA level. More importantly, cell lacking p21WAF1by siRNA transfection abolished the inhibitive effect of MG132 on cells proliferation. Our study suggests that accumulation of p21WAF1protein level caused by proteasome inhibition particularly mediated its inhibitive effect on PASMCs proliferation, and inhibition of proteasome function might have potential value in the treatment of pulmonary hypertension.