Tanshinone IIA harmonizes the crosstalk of autophagy and polarization in macrophages via miR-375/KLF4 pathway to attenuate atherosclerosis
Tanshinone IIA harmonizes the crosstalk of autophagy and polarization in macrophages via miR-375/KLF4 pathway to attenuate atherosclerosis
复制标题
丹参酮IIA通过miR-375/KLF 4途径协调巨噬细胞自噬和极化的相互作用减轻动脉粥样硬化
DOI：
10.1016/j.intimp.2019.02.054
复制
发表时间：
2019-05-01
影响因子：
5.6
通讯作者：
Zhu, Aisong
中科院分区：
文献类型：
--
作者：
Chen, Wenna;Li, Ximing;Zhu, Aisong
巨噬细胞在破坏动脉粥样硬化斑块的稳定性中起着关键作用。在动脉粥样硬化病变中可观察到巨噬细胞的不同表型和复杂的自噬。丹参酮IIA(TNA)是从中草药丹参中提取的主要成分，用于治疗心血管疾病。然而，TNA的治疗机制尚不清楚。在本研究中，我们利用基因芯片技术鉴定了高脂饲料喂养的ApoE基因敲除小鼠动脉粥样硬化斑块中炎症相关基因的表达，发现miR-375是与野生型小鼠和TNA处理的小鼠相比显著高表达的microRNAs之一。然后比较与自噬信号通路相关的蛋白质水平，以及体外动脉粥样硬化斑块中巨噬细胞的表型。我们预测KLF4可能是miR-375的关键靶点，通过TNA介导自噬和极化之间的串扰。此外，我们还检测了体外培养的氧化低密度脂蛋白诱导的巨噬细胞经TNA处理后信号通路的表达，以验证这一预测。提示TNA可能通过抑制miR-375抑制动脉粥样硬化而激活KLF4，增强巨噬细胞的自噬和M2极化。
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.