金丝桃苷通过TLR4_NF...动脉粥样硬化小鼠的干预作用_鄂璐莎.pdf

论著基础研究基金项目:内蒙古自治区自然科学基金(2016MS0867)第一作者简介:鄂璐莎，硕士，主任医师，研究方向:冠心病的机制研究。金丝桃苷通过 TL4/NF-B 信号通路对动脉粥样硬化小鼠的干预作用鄂璐莎田志强王婷(内蒙古自治区人民医院心内科，内蒙古呼和浩特市010017)【摘要】目的探讨金丝桃苷通过 Toll 样受体 4(TL4)/核转录因子-B(NF-B)信号通路对动脉粥样硬化小鼠的干预作用。方法将 50 只雄性小鼠随机分为正常组、模型组、金丝桃苷低剂量组、金丝桃苷高剂量组、辛伐他汀组，各 10 只。除正常组小鼠外，其余各组建立动脉粥样硬化小鼠模型。建模完成后，分别给予金丝桃苷低剂量组、金丝桃苷高剂量组、辛伐他汀组小鼠灌胃 30 mg/(kgd)金丝桃苷、60 mg/(kgd)金丝桃苷、辛伐他汀，给予正常组、模型组小鼠灌胃等量生理盐水，连续干预 4 周。采用 HE 染色观察各组小鼠主动脉组织病理学变化。除正常组外，检测其余小鼠斑块成分占比、斑块易损指数、斑块内新生血管密度。检测各组小鼠血清三酰甘油、总胆固醇、HDL-C、白细胞介素(IL)-6、肿瘤坏死因子(TNF-)、IL-8、谷胱甘肽过氧化物酶(GSH-Px)、活性氧簇、超氧化物歧化酶(SOD)、血管内皮生长因子(VEGF)、内皮素 1 水平，以及主动脉组织TL4、NF-B 蛋白表达量。结果相比于正常组，模型组小鼠主动脉内有斑块形成，动脉壁不均匀增厚并发生局部钙化，有大量巨噬细胞和淋巴细胞浸润，且血清 VEGF、内皮素 1、三酰甘油、总胆固醇、IL-6、TNF-、IL-8、活性氧簇水平升高，血清 HDL-C、GSH-Px、SOD 水平均降低，主动脉组织 TL4、NF-B 蛋白表达量均上调(均 P 0 05)。相比于模型组，3 个药物干预组小鼠主动脉壁增厚情况、巨噬细胞和淋巴细胞浸润现象减轻，血清 VEGF、内皮素 1、三酰甘油、总胆固醇、IL-6、TNF-、IL-8、活性氧簇水平均降低，血清 HDL-C、GSH-Px、SOD 水平均升高，主动脉组织 TL4、NF-B 蛋白表达量均下调，且斑块易损指数、斑块内新生血管密度较低(均 P 0 05);金丝桃苷高剂量组与辛伐他汀组的上述指标均优于金丝桃苷低剂量组(均 P 0 05)，但金丝桃苷高剂量组与辛伐他汀组的各项指标差异均无统计学意义(均 P 0 05)。结论金丝桃苷能有效减轻动脉粥样硬化小鼠的炎症反应及氧化应激水平，调节血脂水平，抑制血管新生，修复血管损伤，剂量为 60 mg/(kgd)干预效果更佳。金丝桃苷的作用机制可能与抑制 TL4/NF-B 信号通路的活性有关。【关键词】动脉粥样硬化;金丝桃苷;斑块;新生血管;血脂;氧化应激;炎症反应;Toll 样受体 4;核转录因子-B;小鼠【中图分类号】543 12【文献标识码】A【文章编号】0253-4304(2023)03-0302-07DOI:10 11675/j issn 0253-4304 2023 03 10Intervention effect of hyperoside via TL4/NF-B signaling pathway on mice with atherosclerosisE Lusha，TIAN Zhiqiang，WANG Ting(Department of Cardiology，Peoples Hospital of Inner Mongolia Autonomous egion，Hohhot 010017，Inner Mongolia，China)【Abstract】ObjectiveTo investigate the intervention effect of hyperoside via Toll-like receptor 4(TL4)/nuclearfactor-B(NF-B)signaling pathway on mice with atherosclerosis MethodsFifty male mice were randomly divided intonormal group，model group，low-dose hyperoside group，high-dose hyperoside group，or simvastatin group，with 10 mice ineach group Except for mice in the normal group，atherosclerotic mice models were constructed in the remaining groupsAfter completed modeling，mice in the low-dose hyperoside group，the high-dose hyperoside group，and the simvastatingroup received intragastric administration of 30 mg/(kgd)hyperoside，60 mg/(kgd)hyperoside，and simvastatin，respectively，and mice in the normal group and the model group received intragastric administration of normal salinewith equivalent volume All groups received intervention for 4 weeks Pathological changes of aortic tissues in mice ofvarious groups were observed by HE staining Except for the normal group，the proportion of plaque component，203Guangxi Medical Journal，Feb 2023，Vol 45，No 3vulnerable index of plaque，and microvasculature density of plaque were detected in mice of the remaining groups Thelevels of serum triglyceride，total cholesterol，HDL-C，interleukin(IL)-6，tumor necrosis factor (TNF-)，IL-8，glutathione peroxidase(GSH-Px)，reactive oxygen species，superoxide dismutase(SOD)，vascular endothelialgrowth factor(VEGF)，and endothelin 1，as well as protein expressions of TL4 and NF-B in aortic tissues weredetected in mice of various groups esultsCompared with the normal group，mice in the model group presented asplaque formation in aorta，artery wall uneven thickening，occurrence of local calcification，and a large number ofmacrophages and lymphocytes infiltration，and mice in the model group acquired elevated levels of serum VEGF，endothelin 1，triglyceride，total cholesterol，IL-6，TNF-，IL-8，and reactive oxygen species，and decreased levels ofserum HDL-C，GSH-Px，and SOD，as well as up-regulated protein expressions of TL4 and NF-B in aortictissues(all P 0 05)Compared with the model group，mice in the 3 drug-intervened groups presented as aorticwall thickening，macrophages and lymphocytes infiltration relieving，and mice in these groups obtained decreasedlevels of serum VEGF，endothelin 1，triglyceride，total cholesterol，IL-6，TNF-，IL-8，and reactive oxygen species，elevated levels of serum HDL-C，GSH-Px，and SOD，down-regulated protein expressions of TL4 and NF-B inaortic tissues，as well as lower vulnerable index of plaque and microvasculature density of plaque(all P 0 05)Theaforementioned indices in the high-dose hyperoside and the simvastatin groups were superior to those in the low-dosehyperoside group(all P 005);however，there was no statistically significant difference in various indices betweenthe high-dose hyperoside group and the simvastatin group(all P 0 05)ConclusionHyperoside can effectivelyrelieve inflammatory response and oxidative stress levels in atherosclerotic mice，modulate blood lipid levels，inhibitangiogenesis，and repair vascular damage，and the optimal intervention effect goes to 60 mg/(kgd)dose Themechanism of hyperoside may be related to inhibit activity of TL4/NF-B signaling pathway【Key words】Atherosclerosis，Hyperoside，Plaque，Angiogenesis，Blood lipid，Oxidative stress，Inflammatoryresponse，Toll-like receptor 4，Nuclear factor-B，Mice动脉粥样硬化是一种慢性炎性疾病，是心脑血管疾病较常见的类型，可由高血压、糖尿病、高血脂等多种因素诱发1，同时又可增加心脑血管并发症的发生率2 3。血管内膜受损是动脉粥样硬化的始发因素，炎症是动脉粥样硬化发展的中心环节。粥样硬化斑块的病理特征包括血管内皮受损、脂质代谢紊乱、炎性浸润、血栓形成等4。近年来，动脉粥样硬化的发病率逐年上升