State Key Laboratory of Cardiovascular Disease, FuWai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College, Chinese Academy of Medical Sciences, Beilishi Road 167, Xicheng District, Beijing 100037, China.
Department of Radiology, FuWai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beilishi Road 167, Xicheng District, Beijing 100037, China.
Biochim Biophys Acta Mol Basis Dis. 2019 Jul 1;1865(7):1772-1781. doi: 10.1016/j.bbadis.2018.06.016. Epub 2018 Jun 27.
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-κB), 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/NF-κB 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/NF-κB pathway. miR-216a also induced macrophages senescence characterized by senescence-associated-β-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-κB signaling, which might serve as a potential therapeutic target for atherosclerosis progression.
巨噬细胞表现出异质性和可塑性，促炎型和抗炎型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-κB（NF-κB）可激活巨噬细胞中的端粒酶逆转录酶（TERT），但端粒酶激活对巨噬细胞极化的调节尚不清楚。我们之前发现 microRNA-216a（miR-216a）可通过直接靶向 Smad3/NF-κB 通路促进炎症。本研究旨在评估 miR-216a 是否可以调节动脉粥样硬化进展过程中巨噬细胞中的端粒酶活性并促进其极化。结果证实 TERT 在人颈动脉粥样硬化斑块中的巨噬细胞中高表达。研究发现 miR-216a 通过 Smad3/NF-κB 通路将端粒酶活性在巨噬细胞中上调 4.5 倍（P=0.002）。miR-216a 还诱导巨噬细胞衰老，其特征为衰老相关-β-半乳糖苷酶活性以及 p53 和 p16 的表达。TERT 过表达促进 M2 向 M1 的转化，而当 TERT 被抑制时，这种转化受到抑制，M1 细胞的相关炎症因子和脂质摄取能力也增加。在 miR-216a 处理的载脂蛋白 E 小鼠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，同时伴有 Smad3 表达抑制和炎症标志物及 TERT 活性上调。此外，在易损混合斑块患者（n=181）的血浆 miR-216a 水平明显高于钙化斑块患者（n=73）和对照组（n=264）。总之，我们的研究结果首次揭示了一种新的分子机制，即 miR-216a 通过 Smad3/NF-κB 信号诱导端粒酶激活，从而导致巨噬细胞极化，这可能成为动脉粥样硬化进展的潜在治疗靶点。
