Chen Zhuo, Gao Xiang, Jiao Yang, Qiu Yu, Wang Anlu, Yu Meili, Che Fangyuan, Li Siming, Liu Jing, Li Jingen, Zhang He, Yu Changan, Li Geng, Gao Yanxiang, Pan Lin, Sun Weiliang, Guo Jing, Cao Bingyan, Zhu Yilin, Xu Hao
Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
Internal medicine, Tieying Hospital of Fengtai District, Beijing, China.
Front Pharmacol. 2019 Jul 26;10:850. doi: 10.3389/fphar.2019.00850. eCollection 2019.
Tanshinone IIA (Tan IIA), a lipophilic constituent from Bunge, has shown a promising cardioprotective effect including anti-atherosclerosis. This study aims at exploring Tan IIA's anti-inflammatory and immune-regulating roles in stabilizing vulnerable atherosclerotic plaque in ApoE-deficient (ApoE) mice. Male ApoE mice (6 weeks) were fed with a high-fat diet for 13 weeks and then randomized to the model group (MOD) or Tan IIA groups [high dose: 90 mg/kg/day (HT), moderate dose: 30 mg/kg/day (MT), low dose: 10 mg/kg/day (LT)] or the atorvastatin group (5 mg/kg/day, ATO) for 13 weeks. Male C57BL/6 mice (6 weeks) were fed with ordinary rodent chow as control. The plaque stability was evaluated according to the morphology and composition of aortic atherosclerotic (AS) plaque in H&E staining and Movat staining sections by calculating the area of extracellular lipid, collagenous fiber, and foam cells to the plaque. The expression of the Toll-like receptor 4 (TLR4)/myeloid differentiation factor88 (MyD88)/nuclear factor-kappa B (NF-κB) signal pathway in aorta fractions was determined by immunohistochemistry. Serum levels of blood lipid were measured by turbidimetric inhibition immunoassay. The concentrations of tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) were detected by cytometric bead array. Tan IIA stabilized aortic plaque with a striking reduction in the area of extracellular lipid (ATO: 13.15 ± 1.2%, HT: 12.2 ± 1.64%, MT: 13.93 ± 1.59%, MOD: 18.84 ± 1.46%, < 0.05) or foam cells (ATO: 16.05 ± 1.26%, HT: 14.88 ± 1.79%, MT: 16.61 ± 1.47%, MOD: 22.08 ± 1.69%, < 0.05) to the plaque, and an evident increase in content of collagenous fiber (ATO: 16.22 ± 1.91%, HT: 17.58 ± 1.33%, MT: 15.71 ± 2.26%, LT:14.92 ± 1.65%, MOD: 9.61 ± 0.7%, < 0.05) to the plaque than that in the model group, concomitant with down-regulation of the protein expression of TLR4, MyD88, and NF-κB p65, and serum level of MCP-1 and TNF-α in a dose-dependent manner. There were no differences in serum TC, LDL, HDL, or TG levels between ApoE mice and those treated with atorvastatin. These results suggest that Tan IIA could stabilize vulnerable AS plaque in ApoE mice, and this anti-inflammatory and immune-regulating effect may be achieved the TLR4/MyD88/NF-κB signaling pathway.
丹参酮IIA（Tan IIA）是丹参中的一种亲脂性成分，已显示出包括抗动脉粥样硬化在内的有前景的心脏保护作用。本研究旨在探讨Tan IIA在稳定载脂蛋白E缺陷（ApoE）小鼠易损动脉粥样硬化斑块中的抗炎和免疫调节作用。将雄性ApoE小鼠（6周龄）高脂喂养13周，然后随机分为模型组（MOD）、Tan IIA组[高剂量：90 mg/kg/天（HT）、中剂量：30 mg/kg/天（MT）、低剂量：10 mg/kg/天（LT）]或阿托伐他汀组（5 mg/kg/天，ATO），持续13周。将雄性C57BL/6小鼠（6周龄）喂以普通啮齿动物饲料作为对照。通过计算细胞外脂质、胶原纤维和泡沫细胞在斑块中的面积，根据苏木精-伊红（H&E）染色和莫瓦特（Movat）染色切片中主动脉动脉粥样硬化（AS）斑块的形态和组成来评估斑块稳定性。通过免疫组织化学测定主动脉部分中Toll样受体4（TLR4）/髓样分化因子88（MyD88）/核因子-κB（NF-κB）信号通路的表达。通过比浊抑制免疫测定法测量血清血脂水平。通过细胞计数珠阵列检测肿瘤坏死因子-α（TNF-α）和单核细胞趋化蛋白-1（MCP-1）的浓度。Tan IIA使主动脉斑块稳定化，斑块中细胞外脂质（ATO：13.15±1.2%，HT：12.2±1.64%，MT：13.93±1.59%，MOD：18.8～4±1.46%，P<0.05）或泡沫细胞（ATO：16.05±1.26%，HT：14.88±1.79%，MT：16.61±1.47%，MOD：22.08±1.69%，P<0.05）的面积显著减少，与模型组相比，斑块中胶原纤维含量明显增加（ATO：16.22±1.91%，HT：17.58±1.33%，MT：15.71±2.26%，LT：14.92±1.65%，MOD：9.61±0.7%），同时TLR4、MyD88和NF-κB p65的蛋白表达以及血清MCP-1和TNF-α水平呈剂量依赖性下调。ApoE小鼠与接受阿托伐他汀治疗的小鼠之间的血清总胆固醇（TC）、低密度脂蛋白（LDL）、高密度脂蛋白（HDL）或甘油三酯（TG）水平无差异。这些结果表明，Tan IIA可稳定ApoE小鼠的易损AS斑块，且这种抗炎和免疫调节作用可能通过TLR4/MyD88/NF-κB信号通路实现。
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