CKII-SIRT1-SM22α loop evokes a self-limited inflammatory response in vascular smooth muscle cells
CKII-SIRT1-SM22α loop evokes a self-limited inflammatory response in vascular smooth muscle cells
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CKII-SIRT1-SM22 环在血管平滑肌细胞中引起自限性炎症反应
DOI：
10.1093/cvr/cvx048
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发表时间：
2017-08-01
影响因子：
10.8
通讯作者：
Han, Mei
中科院分区：
文献类型：
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作者：
Shu, Ya-Nan;Dong, Li-Hua;Han, Mei
目的Sirtuin 1(SIRT1)抑制炎性细胞因子肿瘤坏死因子-α(TNF-α)对核因子-kappaB(NF-kappa B)的活性。平滑肌(SM)22α是血管平滑肌细胞(VSMCs)中IKK-I-kappa Bα-核因子-kappa B信号转导通路的磷酸化调节抑制因子。结果Sirt1-TG/Sm22α(-/-)小鼠颈动脉结扎损伤模型颈动脉炎症分子水平明显高于Sirt1-TG小鼠，并伴有新生内膜增生。在体外研究中，我们一方面表明，肿瘤坏死因子-α通过EZH2介导的SM22α启动子区域H3K27甲基化，诱导了SM22α转录的表观遗传沉默，从而促进了炎症反应。另一方面，肿瘤坏死因子-α通过CKII同时诱导SIRT1的磷酸化，从而对炎症具有保护作用。磷酸化的SIRT1与EZH2相互作用并去乙酰化，随后通过抑制EZH2的活性促进SM22α的转录。SIRT1通过募集CKII促进SIRT1的磷酸化和活化，从而增强SIRT1的抗炎作用。结论CKII-SIRT1-SM22α在肿瘤坏死因子-α刺激下环路增强SM22α的表达，从而限制了体内外VSMC的炎症反应。SIRT1的抗炎作用可能在一定程度上依赖于SM22α。我们的数据表明，靶向激活血管平滑肌细胞中的SIRT1是预防心血管疾病的一种有前途的治疗途径。
Aims Sirtuin 1 (SIRT1) inhibits nuclear factor kappa B (NF-kappa B) activity in response to the inflammatory cytokine tumour necrosis factor alpha (TNF-alpha). Smooth muscle (SM) 22 alpha is a phosphorylation-regulated suppressor of IKK-I kappa B alpha-NF-kappa B signalling cascades in vascular smooth muscle cells (VSMCs). Sm22 alpha knockout results in increased expression of pro-inflammatory genes in the aortas which are controlled by NF-kappa B. This study aimed to investigate the relationship between SM22 alpha and SIRT1 in the control of vascular inflammation.Methods and results The ligation injury model of Sirt1-Tg/Sm22 alpha(-/-) 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-alpha induced the epigenetic silencing of SM22 alpha transcription via EZH2-mediated H3K27 methylation in the SM22 alpha promoter region, contributing to inflammatory response. On the other hand, TNF-alpha simultaneously induced SIRT1 phosphorylation via CKII and thereby protected against inflammation. Phosphorylated SIRT1 interacted with and deacetylated EZH2 and, subsequently, promoted SM22 alpha transcription by inhibiting EZH2 activity. Increased SM22 alpha in turn facilitated the phosphorylation and activation of SIRT1 via recruitment of CKII to SIRT1, which amplified the anti-inflammatory effect of SIRT1.Conclusion Our findings demonstrate that, in response to TNF-alpha stimulation, CKII-SIRT1-SM22 alpha acts in a loop to reinforce the expression of SM22 alpha, which limits the inflammatory response in VSMCs in vivo and in vitro. The anti-inflammatory effect of SIRT1 may be dependent on SM22 alpha to some extent. Our data point to targeted activation of SIRT1 in VSMCs as a promising therapeutic avenue in preventing cardiovascular diseases.