MicroRNA-216a promotes M1 macrophages polarization and atherosclerosis progression by activating telomerase via the Smad3/NF-κB pathway
MicroRNA-216a promotes M1 macrophages polarization and atherosclerosis progression by activating telomerase via the Smad3/NF-κB pathway
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MicroRNA-216a 通过 Smad3/NF-kappa B 途径激活端粒酶，促进 M1 巨噬细胞极化和动脉粥样硬化进展
DOI：
10.1016/j.bbadis.2018.06.016
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发表时间：
2019-07-01
影响因子：
6.2
通讯作者：
Zhang, Weili
中科院分区：
文献类型：
--
作者：
Yang, Shujun;Li, Jian;Zhang, Weili
巨噬细胞具有异质性和可塑性，促炎和抗炎巨噬细胞之间的失衡在动脉粥样硬化进展中起着关键作用。核因子-κ B（NF-κ B B）可激活巨噬细胞的端粒酶逆转录酶（TERT），但其对巨噬细胞极化的调控作用尚不清楚。我们先前鉴定了microRNA-216 a（miR-216 a）通过直接靶向Smad 3/NE-κ B通路来促进炎症。本研究旨在评估miR-216 a在动脉粥样硬化进展过程中是否可以调节端粒酶活性并促进巨噬细胞极化。结果证实，人颈动脉粥样硬化斑块巨噬细胞中高表达TERT。发现miR-216 a通过Smad 3/NE-κ B途径促进巨噬细胞中端粒酶活化4.5倍（P = 0.002）。miR-216 a还诱导巨噬细胞衰老，其特征在于衰老相关的β-半乳糖苷酶活性和p53和p16表达。TERT过表达可促进M2向M1转化，而抑制TERT则可抑制M2向M1的转化，并可增加M1细胞的相关炎症因子和脂质摄取能力。在miR-216 a处理的载脂蛋白E-/-小鼠的颈动脉粥样硬化斑块中，M1巨噬细胞数量增加，而M2细胞减少，同时Smad 3表达受到抑制，炎症标志物和TERT活性上调。此外，血浆miR-216 a水平在易损混合斑块患者（n = 181）中特别高于钙化斑块患者（n = 73）和对照组（n = 264）。综上所述，我们的研究结果首次揭示了miR-216 a通过Smad 3/NF-κ B信号通路诱导的端粒酶活化参与巨噬细胞极化的新分子机制，这可能成为动脉粥样硬化进展的潜在治疗靶点。
Macrophages exhibit heterogeneity and plasticity and imbalance between pro-inflammatory and anti-inflammatory macrophages plays a critical role in atherosclerosis progression. Telomerase reverse transcriptase (TERT) in macrophages can be activated by nuclear factor-kappa B (NF-kappa B), but the regulation of telomerase activation on macrophages polarization remains unknown. We previously identified microRNA-216a (miR-216a) to promote inflammation through directly targeting the Smad3/NE-kappa B pathway. The present study aimed to assess whether miR-216a can regulate telomerase activity and promote macrophages polarization during atherosclerosis progression. The results verified that TERT was highly expressed in macrophages of human carotid atherosclerotic plaques. miR-216a was found to promote telomerase activation in macrophages by 4.5-fold (P = 0.002) through the Smad3/NE-kappa B pathway. miR-216a also induced macrophages senescence characterized by senescence-associated-beta-galactosidase activity and p53 and p16 expression. TERT overexpression promoted the transformation of M2 to M1 while this conversion was suppressed once TERT was inhibited, and the related inflammatory factors and lipid uptake ability of M1 cells were also increased by TERT. In the carotid atherosclerotic plaques from miR-216a-treated apolipoprotein E-/- mice, the numbers of M1 macrophages were increased whereas M2 cells reduced, accompanying with inhibited Smad3 expression and upregulated inflammatory markers and TERT activity. Furthermore, plasma miR-216a level was specifically higher in patients with vulnerable mixed plaques (n = 181) than those with calcified plaques (n = 73) and controls (n = 264). In summary, our findings first revealed a new molecular mechanism of macrophage polarization involving telomerase activation induced by miR-216a through the Smad3/NF-kappa B signaling, which might serve as a potential therapeutic target for atherosclerosis progression.