Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Medical Biotechnology of Hebei Province, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang 050017, PR China.
Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Medical Biotechnology of Hebei Province, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang 050017, PR China; Department of Biochemistry and Molecular Biology, National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, PR China.
J Mol Cell Cardiol. 2014 Jul;72:263-72. doi: 10.1016/j.yjmcc.2014.04.003. Epub 2014 Apr 13.
Smooth muscle cell marker, SM22α, 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 SM22α, here we explored transcriptome profiling by RNA-Seq from arteries of SM22α(-/-) and SM22α(+/+) mice. Analysis revealed that the most enriched pathways caused by SM22α-knockout were hematopoiesis, inflammation and lipid metabolism, respectively, and NF-κB, RXRα and PPARα 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 SM22α(-/-) mice was already prepared for the initiation of atherosclerosis. Further analysis suggested the up-regulated TNF caused NF-κB pathway activation. Our results showed loss of SM22α exacerbated TNF-α-mediated NF-κB activation and increased the expression levels of ApoCI in vitro, while overexpression of SM22α suppressed TNF-α-mediated NF-κB activation. In addition, disruption of SM22α 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 SM22α can actively contribute to the pathogenesis of atherosclerosis from the molecular basis, but also further confirmed that the vascular cells of SM22α(-/-) mice may become more sensitive to extracellular stimulation, increasing its tendency to develop vascular diseases. Meanwhile, rescuing SM22α expression may provide a novel therapeutic strategy for arterial diseases.
平滑肌细胞标志物 SM22α 在包括动脉粥样硬化、再狭窄和腹主动脉瘤在内的动脉疾病的发病机制中下调。然而，SM22α 的下调是否积极促进血管疾病的发病机制仍然存在问题。为了深入了解 SM22α 的作用，我们在这里通过 RNA-Seq 从 SM22α(-/-)和 SM22α(+/+)小鼠的动脉中探索了转录组谱。分析表明，SM22α 敲除引起的最丰富的途径分别是造血、炎症和脂质代谢，NF-κB、RXRα 和 PPARα 是主要的上游调节因子。涉及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 SM22α(-/-)小鼠中的分子基础已经为动脉粥样硬化的发生做好了准备。进一步的分析表明，上调的 TNF 导致 NF-κB 通路的激活。我们的研究结果表明，SM22α 的缺失加剧了 TNF-α 介导的 NF-κB 激活，并增加了体外 ApoCI 的表达水平，而 SM22α 的过表达抑制了 TNF-α 介导的 NF-κB 激活。此外，SM22α 的破坏增强了损伤诱导的新生内膜增生，并增加了与细胞黏附和细胞外基质降解相关的分子的表达水平。总之，这些发现不仅表明 SM22α 的下调可以从分子基础上积极促进动脉粥样硬化的发病机制，而且还进一步证实了 SM22α(-/-)小鼠的血管细胞可能对细胞外刺激更加敏感，增加了其发生血管疾病的倾向。同时，恢复 SM22α 的表达可能为动脉疾病提供一种新的治疗策略。
