Transcriptome profiling reveals that the SM22α-regulated molecular pathways contribute to vascular pathology
Transcriptome profiling reveals that the SM22α-regulated molecular pathways contribute to vascular pathology
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DOI：
10.1016/j.yjmcc.2014.04.003
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发表时间：
2014-07-01
影响因子：
5
通讯作者：
Han, Mei
中科院分区：
文献类型：
--
作者：
Chen, Rong;Zhang, Fan;Han, Mei
平滑肌细胞标志物SM22 α在动脉粥样硬化、再狭窄和腹主动脉瘤等动脉疾病的发病机制中下调。然而，这种下调是否积极参与血管疾病的发病机制仍然是一个问题。为了进一步了解SM22 α的作用，我们利用RNA-Seq对SM22 α(-/-)和SM22 α(+/+)小鼠的动脉进行了转录组分析。分析发现，SM22 α敲除引起的最富集的途径分别是造血、炎症和脂质代谢，NF-kappa B、RXR α和PPAR α是主要的上游调控因子。参与炎症和脂质代谢的候选基因聚集在动脉粥样硬化中。因此，我们怀疑SM22 α(-/-)小鼠的分子基础已经为动脉粥样硬化的启动做好了准备。进一步分析表明，TNF上调引起NF-kappa B通路激活。我们的研究结果显示，SM22 α的缺失加剧了tnf - α介导的NF-kappa B的激活，增加了体外ApoCI的表达水平，而SM22 α的过表达抑制了tnf -a介导的NF-kappa B的激活。此外，SM22 α的破坏增强了损伤诱导的内膜增生，并增加了与细胞粘附和细胞外基质降解相关的分子的表达水平。综上所述，这些发现不仅提示SM22 α的下调可以从分子基础上积极参与动脉粥样硬化的发病，而且进一步证实SM22 α(-/-)小鼠的血管细胞可能对细胞外刺激更加敏感，增加其发生血管疾病的倾向。同时，挽救SM22 α的表达可能为动脉疾病的治疗提供新的策略。(C) 2014年作者。Elsevier Ltd.出版。
Smooth muscle cell marker, SM22 alpha, was down-regulated in the pathogenesis of arterial diseases including atherosclerosis, restenosis and abdominal aortic aneurysms. However, the question still exists whether this down-regulation actively contributes to the pathogenesis of vascular diseases. In an ongoing effort to understand the role of SM22 alpha, here we explored transcriptome profiling by RNA-Seq from arteries of SM22 alpha(-/-) and SM22 alpha(+/+) mice. Analysis revealed that the most enriched pathways caused by SM22 alpha-knockout were hematopoiesis, inflammation and lipid metabolism, respectively, and NF-kappa B, RXR alpha and PPAR alpha were the major upstream regulators. The candidate genes involved in inflammation and lipid metabolism were clustered in atherosclerosis. Thus we suspected that the molecular basis in SM22 alpha(-/-) mice was already prepared for the initiation of atherosclerosis. Further analysis suggested the up-regulated TNF caused NF-kappa B pathway activation. Our results showed loss of SM22 alpha exacerbated TNF-alpha-mediated NF-kappa B activation and increased the expression levels of ApoCI in vitro, while overexpression of SM22 alpha suppressed TNF-a-mediated NF-kappa B activation. In addition, disruption of SM22 alpha enhanced injury-induced neointimal hyperplasia, and increased expression levels of molecules related with cellular adhesion and extracellular matrix degradation. Taken together, these findings not only suggested down-regulation of SM22 alpha can actively contribute to the pathogenesis of atherosclerosis from the molecular basis, but also further confirmed that the vascular cells of SM22 alpha(-/-) mice may become more sensitive to extracellular stimulation, increasing its tendency to develop vascular diseases. Meanwhile, rescuing SM22 alpha expression may provide a novel therapeutic strategy for arterial diseases. (C) 2014 The Authors. Published by Elsevier Ltd.