隐丹参酮通过Dectin-1信号通路调节巨噬细胞极化抗心肌缺血损伤作用及机制研究  

Anti-myocardial ischemic injury effects and mechanisms of cryptotanshinone in regulating macrophage polarisation through Dectin-1 signalling pathway

作　　者：范玉鸣 方乐玉 房志锐 李梦瑶 石婷婷 郭滢 陈璐[2] 王虹[1] FAN Yu-ming;FANG Le-yu;FANG Zhi-rui;LI Meng-yao;SHI Ting-ting;GUO Ying;CHEN Lu;WANG Hong(School of Medical Technology,Tianjin University of Traditional Chinese Medicine,Tianjin 301617,China;Testing Centre,Tianjin University of Traditional Chinese Medicine,Tianjin 301617,China)

机构地区：[1]天津中医药大学医学技术学院,天津301617 [2]天津中医药大学测试中心,天津301617

出　　处：《中国中药杂志》2024年第14期3901-3911,共11页China Journal of Chinese Materia Medica

基　　金：国家自然科学基金面上项目(82274135,82174205)。

摘　　要：探讨隐丹参酮(cryptotanshinone,CTS)是否通过树突状细胞相关C型凝集素1(Dectin^(-1))信号通路调节巨噬细胞极化发挥抗心肌缺血的作用。选用6周龄雄性C57BL/6小鼠制作心肌缺血模型,分为假手术组、模型组、CTS低剂量组(21 mg·kg^(-1)·d^(-1))、CTS高剂量组(84 mg·kg^(-1)·d^(-1))、达格列嗪组(0.14 mg·kg^(-1)·d^(-1))。分别检测各组心功能和血清酶水平、Dectin^(-1)表达以及心肌梗死区巨噬细胞极化和中性粒细胞浸润程度。进一步利用脂多糖(lipopolysaccharide,LPS)/干扰素(interferon,IFN)-γ刺激RAW264.7构建M1型巨噬细胞体外模型,观察CTS对巨噬细胞极化状态的影响,并检测Dectin^(-1)信号通路下游关键蛋白的变化。CTS组相比模型组小鼠,心功能和心肌损伤程度均明显改善,心肌梗死区M2/M1型巨噬细胞比例显著升高,中性粒细胞浸润明显减少,同时Dectin^(-1)呈现低表达。体外实验显示,CTS可下调M1型并升高M2型标志基因的表达,并降低Dectin^(-1)的含量及其通路相关蛋白脾酪氨酸激酶(spleen tyrosine kinase,Syk)、蛋白激酶B(protein kinase B,Akt)、核因子-κB p65(nuclear factor-kappaB p65,NF-κB p65)和细胞外调节蛋白激酶(extracellular regulated protein kinases,ERK)1/2的磷酸化,促进信号传导及转录激活蛋白(signal transducer and activator of transcription,STAT)6的磷酸化。结果表明隐丹参酮通过Dectin^(-1)信号通路调节巨噬细胞极化发挥抗心肌缺血损伤作用。The aim of this study was to investigate the potential mechanism by which cryptotanshinone(CTS) may exert its anti-myo-cardial ischemic effect through the regulation of macrophage polarization via the dendritic cell-associated C-type lectin 1(Dectin-1) signaling pathway. Male C57BL/6 mice, aged six weeks, were utilized to establish myocardial ischemia models and were subsequently divided into five groups: sham, model, CTS low-dose(21 mg·kg^(-1)·d^(-1)), CTS high-dose(84 mg·kg^(-1)·d^(-1)), and dapagliflozin(0.14 mg·kg^(-1)·d^(-1)). The cardiac function, serum enzyme levels, Dectin-1 expression, macrophage polarization, and neutrophil infiltration in the myocardial infarction area were assessed in each group. An in vitro model of M1-type macrophages was constructed using lipopolysaccharide/interfe-ron-γ(LPS/IFN-γ) stimulated RAW264.7 cells to investigate the impact of CTS on macrophage polarization and to examine alterations in key proteins within the Dectin-1 signaling pathway. In the CTS group, compared to the model group mice, there was a significant improvement in the cardiac function and myocardial injury, along with a notable increase in the ratio of M2/M1-type macrophages in the myocardial infarcted area and a decrease in neutrophil infiltration. Additionally, Dectin-1 exhibited low expression. The results of in vitro experiments demonstrated that CTS can decrease the expression of M1-type marker genes and increase the expression of M2-type marker genes. Besides, it can decrease the levels of Dectin-1 and the phosphorylation of its associated proteins, including spleen tyrosine kinase(Syk), protein kinase B(Akt), nuclear factor-kappaB p65(NF-κB p65), and extracellular signal-regulated protein kinases(ERK1/2). Additionally, CTS was found to enhance the phosphorylation of signal transducer and activator of transcription-6(STAT6). The above results suggest that CTS exerts its anti-myocardial ischemic injury effect by regulating macrophage polarization through the Dectin-1 signaling pathway.

关 键 词：隐丹参酮 巨噬细胞极化 DECTIN-1 炎症 心肌梗死 

分 类 号：R285.5[医药卫生—中药学]