Proteomic analysis reveals that proteasome subunit beta 6 is involved in hypoxia-induced pulmonary vascular remodeling in rats.
Proteomic analysis reveals that proteasome subunit beta 6 is involved in hypoxia-induced pulmonary vascular remodeling in rats.
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蛋白质组学分析揭示蛋白酶体亚基 Beta 6 参与缺氧诱导的大鼠肺血管重塑
DOI：
10.1371/journal.pone.0067942
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Lu W
中科院分区：
文献类型：
--
作者：
Wang J;Xu L;Yun X;Yang K;Liao D;Tian L;Jiang H;Lu W
研究背景慢性缺氧（CH）是肺动脉高压（PH）的主要原因之一，其特征是肺血管阻力持续升高，导致肺血管重构。本研究旨在探讨泛素蛋白酶体系统（UPS）是否参与了低氧诱导的肺血管重构的机制。我们分离的远端肺动脉（PA）从以前定义的慢性缺氧性肺动脉高压（CHPH）大鼠模型，进行蛋白质组学分析，寻找差异表达的蛋白属于UPS，随后确定其在动脉重塑中的作用。结果22种蛋白质在CH组和常氧组间表达差异。其中，蛋白酶体β亚基（PSMB）1和PSMB 6的表达在CH暴露后增加。考虑到PSMB 1是一个众所周知的结构亚基，PSMB 6是一个功能亚基，我们试图评估PSMB 6是否与CHPH过程中的多种功能变化有关。我们通过实时荧光PCR和Western blot证实了蛋白质组学结果。培养的肺动脉平滑肌细胞（PASMCs）和缺氧组分离的肺原纤维素（PA）的蛋白酶体活性均随活性亚基数量的增加而增加。MTT法显示，蛋白酶体抑制剂MG 132能够以剂量依赖的方式减弱缺氧诱导的PASMC增殖。使用siRNA敲低PSMB 6也阻止了缺氧诱导的增殖。结论PSMB 6与CHPH的发生有关。CH上调PASMCs的蛋白酶体活性和增殖，这可能与PSMB 6表达增加以及随后蛋白酶体功能催化位点的增强有关。这些结果表明，蛋白酶体在CHPH发展过程中发挥着重要作用，这是一个需要进一步研究的新发现。
Background Chronic hypoxia (CH) is known to be one of the major causes of pulmonary hypertension (PH), which is characterized by sustained elevation of pulmonary vascular resistance resulting from vascular remodeling. In this study, we investigated whether the ubiquitin proteasome system (UPS) was involved in the mechanism of hypoxia-induced pulmonary vascular remodeling. We isolated the distal pulmonary artery (PA) from a previously defined chronic hypoxic pulmonary hypertension (CHPH) rat model, performed proteomic analyses in search of differentially expressed proteins belonging to the UPS, and subsequently identified their roles in arterial remodeling. Results Twenty-two proteins were differently expressed between the CH and normoxic group. Among them, the expression of proteasome subunit beta (PSMB) 1 and PSMB6 increased after CH exposure. Given that PSMB1 is a well-known structural subunit and PSMB6 is a functional subunit, we sought to assess whether PSMB6 could be related to the multiple functional changes during the CHPH process. We confirmed the proteomic results by real-time PCR and Western blot. With the increase in quantity of the active subunit, proteasome activity in both cultured pulmonary artery smooth muscle cells (PASMCs) and isolated PA from the hypoxic group increased. An MTT assay revealed that the proteasome inhibitor MG132 was able to attenuate the hypoxia-induced proliferation of PASMC in a dose-dependent manner. Knockdown of PSMB6 using siRNA also prevented hypoxia-induced proliferation. Conclusion The present study revealed the association between increased PSMB6 and CHPH. CH up-regulated proteasome activity and the proliferation of PASMCs, which may have been related to increased PSMB6 expression and the subsequently enhanced functional catalytic sites of the proteasome. These results suggested an essential role of the proteasome during CHPH development, a novel finding requiring further study.
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