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, No. 361 Zhongshan East Road, Changan District, Shijiazhuang 050017, PR China.
Cardiovasc Res. 2017 Aug 1;113(10):1198-1207. doi: 10.1093/cvr/cvx048.
Sirtuin 1 (SIRT1) inhibits nuclear factor kappa B (NF-κB) activity in response to the inflammatory cytokine tumour necrosis factor alpha (TNF-α). Smooth muscle (SM) 22α is a phosphorylation-regulated suppressor of IKK-IκBα-NF-κB signalling cascades in vascular smooth muscle cells (VSMCs). Sm22α knockout results in increased expression of pro-inflammatory genes in the aortas which are controlled by NF-κB. This study aimed to investigate the relationship between SM22α and SIRT1 in the control of vascular inflammation.
The ligation injury model of Sirt1-Tg/Sm22α-/- mice displayed an increased level of the inflammatory molecules in the carotid arteries compared with Sirt1-Tg mice, accompanied with aggravating neointimal hyperplasia. In the in vitro study, on the one hand, we showed that TNF-α induced the epigenetic silencing of SM22α transcription via EZH2-mediated H3K27 methylation in the SM22α promoter region, contributing to inflammatory response. On the other hand, TNF-α simultaneously induced SIRT1 phosphorylation via CKII and thereby protected against inflammation. Phosphorylated SIRT1 interacted with and deacetylated EZH2 and, subsequently, promoted SM22α transcription by inhibiting EZH2 activity. Increased SM22α in turn facilitated the phosphorylation and activation of SIRT1 via recruitment of CKII to SIRT1, which amplified the anti-inflammatory effect of SIRT1.
Our findings demonstrate that, in response to TNF-α stimulation, CKII-SIRT1-SM22α acts in a loop to reinforce the expression of SM22α, which limits the inflammatory response in VSMCs in vivo and in vitro. The anti-inflammatory effect of SIRT1 may be dependent on SM22α to some extent. Our data point to targeted activation of SIRT1 in VSMCs as a promising therapeutic avenue in preventing cardiovascular diseases.
Sirtuin 1（SIRT1）可抑制核因子 kappa B（NF-κB）活性，以响应炎症细胞因子肿瘤坏死因子-α（TNF-α）。平滑肌 22α（SM22α）是血管平滑肌细胞（VSMCs）中 IKK-IκBα-NF-κB 信号级联反应的磷酸化调节抑制剂。SM22α 敲除会导致 NF-κB 控制的主动脉中促炎基因的表达增加。本研究旨在探讨 SM22α 与 SIRT1 在血管炎症控制中的关系。
Sirt1-Tg/Sm22α-/-小鼠的结扎损伤模型显示，与 Sirt1-Tg 小鼠相比，颈动脉中的炎症分子水平升高，伴随新生内膜过度增生加重。在体外研究中，一方面，我们表明 TNF-α 通过 EZH2 介导的 SM22α 启动子区域 H3K27 甲基化诱导 SM22α 转录的表观遗传沉默，导致炎症反应。另一方面，TNF-α 同时通过 CKII 诱导 SIRT1 磷酸化，从而起到抗炎作用。磷酸化的 SIRT1 与 EZH2 相互作用并去乙酰化 EZH2，随后通过招募 CKII 到 SIRT1 来促进 SM22α 转录，从而增强 SIRT1 的抗炎作用。增加的 SM22α 反过来通过招募 CKII 到 SIRT1 促进 SIRT1 的磷酸化和激活，从而放大 SIRT1 的抗炎作用。
我们的研究结果表明，在 TNF-α 刺激下，CKII-SIRT1-SM22α 以循环方式起作用，增强 SM22α 的表达，从而限制体内和体外 VSMCs 的炎症反应。SIRT1 的抗炎作用在某种程度上可能依赖于 SM22α。我们的数据表明，靶向激活 VSMCs 中的 SIRT1 可能是预防心血管疾病的一种有前途的治疗途径。
