National & Kapodistrian University of Athens, School of Health Sciences, Department of Pharmacy, Laboratory of Biopharmaceutics-Pharmacokinetics, Athens, Greece.
Oxford University, Oxford, United Kingdom.
Atherosclerosis. 2018 Jan;268:207-214. doi: 10.1016/j.atherosclerosis.2017.10.032. Epub 2017 Nov 1.
We aimed to evaluate a possible atheroprotective effect of saffron aqueous extract (SFE), and its potential anti-inflammatory mechanisms, in apoE knockout (ApoE) mice.
Fifty male, ApoE mice, fed a high-fat diet (HFD) for 12 weeks, were randomized into 5 groups: (1) baseline group, euthanatized, without intervention, (2) three saffron groups, receiving HFD and 30,60,90 mg/kg/day of SFE, respectively, for four weeks, per os through gavage, after reconstitution in water for injection (WFI), (3) control group (COG), receiving daily HFD and the same volume of WFI (four weeks). After blood sampling and euthanasia, aortic roots were excised and analyzed for gene expression and/or percentage of aortic stenosis, relative content of macrophages, smooth muscle cells (SMCs), connective tissue, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinases-2,-3,-9 (MMP-2,-3,-9) and their inhibitor (TIMP-2) and IL-6. SFE doses were determined by a pilot serum pharmacokinetic study in C57BL/6J wild-type mice.
SFE did not affect body weight and total cholesterol levels (p > 0.05), while high SFE dose significantly ameliorated glucose and triglycerides profiles compared to other groups (p < 0.05). SFE considerably decreased aortic stenosis in a dose-dependent manner (p < 0.05). Furthermore, increasing SFE doses proportionally reduced macrophages content and increased within plaques content of collagen, elastin, and SMCs, promoting more stable plaque phenotype compared to COG (p < 0.05). Those effects seemed to be associated with a considerable reduction (>30%) in IL-6, TNF-α, MCP-1, MMP-2,-3,-9 (p < 0.05) and MMP-2/TIMP-2 ratio.
SFE exerted dose-dependent anti-atherosclerotic and plaque-stabilizing effects in Apo-E mice, probably mediated by a favorable modification of inflammatory mechanisms, which requires further investigation.
本研究旨在评估藏红花水提物（SFE）对载脂蛋白 E 基因敲除（ApoE）小鼠的可能的抗动脉粥样硬化作用及其潜在的抗炎机制。
50 只雄性 ApoE 小鼠喂食高脂肪饮食（HFD）12 周后，随机分为 5 组：（1）基线组，不经任何干预，安乐死；（2）3 个藏红花组，分别给予 HFD 和 30、60、90mg/kg/天的 SFE，通过灌胃以注射用水（WFI）溶解，连续给药 4 周；（3）对照组（COG），每日给予 HFD 和相同体积的 WFI（4 周）。采血和安乐死后，取出主动脉根部，分析基因表达和/或主动脉狭窄百分比、巨噬细胞、平滑肌细胞（SMCs）、结缔组织、肿瘤坏死因子-α（TNF-α）、单核细胞趋化蛋白-1（MCP-1）、基质金属蛋白酶-2、-3、-9（MMP-2、-3、-9）及其抑制剂（TIMP-2）和 IL-6 的相对含量。藏红花水提物剂量通过 C57BL/6J 野生型小鼠的初步血清药代动力学研究确定。
SFE 不影响体重和总胆固醇水平（p>0.05），而高剂量 SFE 可显著改善血糖和甘油三酯水平，与其他组相比有统计学差异（p<0.05）。SFE 可显著降低主动脉狭窄程度，呈剂量依赖性（p<0.05）。此外，增加 SFE 剂量可相应减少巨噬细胞含量，并增加斑块内胶原、弹性蛋白和 SMCs 的含量，与 COG 相比，更有利于形成稳定的斑块表型（p<0.05）。这些作用可能与白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、单核细胞趋化蛋白-1（MCP-1）、基质金属蛋白酶-2、-3、-9（MMP-2、-3、-9）的显著降低（p<0.05）有关，同时还降低了 MMP-2/TIMP-2 比值。
SFE 对 ApoE 小鼠具有剂量依赖性的抗动脉粥样硬化和稳定斑块作用，可能通过对炎症机制的有利调节来介导，这需要进一步研究。
