Department of Medical Science of Laboratory, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, China; Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, China.
Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, China.
Int Immunopharmacol. 2019 May;70:486-497. doi: 10.1016/j.intimp.2019.02.054. Epub 2019 Mar 12.
Macrophages play a pivotal role in destabilizing atherosclerotic plaque. The diverse phenotypes and complex autophagy in macrophage are observed in atherosclerotic lesions. Tanshinone IIA (TNA) is known as the major component extracted from the root of Chinese herb Salvia miltiorrhiza, used for treatment of cardiovascular diseases. However, the therapeutic mechanism of TNA is not clear yet. In this study, we identified inflammation-related gene expression by microarray in atherosclerotic plaques in ApoE knockout mice fed with high fat diet and found miR-375 was one of the significantly high expressed microRNAs compared with wild type mice and TNA treated mice. Then we compared the levels of proteins related to the signal pathway of autophagy, and the phenotype of macrophages in atherosclerotic plaques ex vivo. We predicted KLF4 might be the key target of miR-375 that mediated the crosstalk between autophagy and polarization by TNA. Furthermore, we detected the expression of signal pathway in ox-LDL induced macrophages after treatment with TNA in vitro to verify this predict. The results suggest TNA could activate KLF4 and enhance autophagy as well as M2 polarization of macrophages by inhibiting miR-375 to Attenuate Atherosclerosis.
巨噬细胞在动脉粥样硬化斑块的不稳定中起着关键作用。在动脉粥样硬化病变中观察到巨噬细胞的表型多样化和复杂的自噬。丹参酮 IIA（TNA）是从中药丹参的根中提取的主要成分，用于治疗心血管疾病。然而，TNA 的治疗机制尚不清楚。在这项研究中，我们通过微阵列鉴定了高脂饮食喂养的载脂蛋白 E 基因敲除小鼠动脉粥样硬化斑块中的炎症相关基因表达，发现与野生型小鼠和 TNA 处理小鼠相比，miR-375 是表达显著升高的 microRNAs 之一。然后，我们比较了动脉粥样硬化斑块中与自噬信号通路相关的蛋白质水平和巨噬细胞的表型。我们预测 KLF4 可能是 miR-375 介导 TNA 自噬与极化之间串扰的关键靶点。此外，我们还检测了 TNA 处理体外 ox-LDL 诱导的巨噬细胞后信号通路的表达，以验证这一预测。结果表明，TNA 通过抑制 miR-375 激活 KLF4 并增强自噬以及巨噬细胞的 M2 极化，从而减轻动脉粥样硬化。
