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医药导报
医药导报, 2020, 39(10): 1331-1335
doi: 10.3870/j.issn.1004-0781.2020.10.002
白杨素对高脂饮食诱导的家兔动脉粥样硬化干预作用研究*
Interventional Effect of Chrysin on Rabbit Atherosclerosis Induced by High Fat Diet
杨波, 胡有志, 张峰, 肖金凤, 胡勇
湖北省中医院心内科,湖北中医药大学,武汉 430061
YANG Bo,, HU Youzhi, ZHANG Feng, XIAO Jinfeng, HU Yong
Department of Cardiology, Hubei Provincial Hospital of TCM, Hubei University of Traditional Chinese Medicine, Wuhan 430061, China

作者简介 杨波(1978-),男,安徽桐城人,副教授,副主任医师,硕士,研究方向:中西医结合治疗心血管病。ORCID:0000-0001-7212-0923,电话:027-88929224,E-mail:156438627@qq.com。
基金资助: 2016—2017年度中医药中西医结合科研项目(鄂卫生计生通〔2017〕20号-58)
中图分类号: R965     文献标识码: A     文章编号: 1004-0781(2020)10-1331-05
摘要:

目的 探讨白杨素对高脂饮食诱导的家兔动脉粥样硬化(AS)干预作用及机制。方法 将24只雄性家兔随机分为3组:正常对照组、模型对照组和白杨素组,每组8只。模型对照组和白杨素组给予高脂饲料建立动脉粥样硬化模型,白杨素组给予白杨素25 mg·kg-1,正常对照组、模型对照组给予等体积0.5%羧甲基纤维素钠混悬液。给药8周后,分别观察血清脂质水平、主动脉病理学变化、主动脉超氧阴离子(O2·-)水平和氧化应激状态。结果 与模型对照组比较,白杨素组家兔血清总胆固醇(TC)、三酰甘油(TG)和低密度脂蛋白胆固醇(LDL-C)水平显著降低(P<0.05),高密度脂蛋白胆固醇(HDL-C)水平升高(P<0.05),主动脉组织病理学变化减轻,主动脉O2·-水平和MDA水平显著降低(P<0.05),SOD活性显著升高(P<0.05)。结论 白杨素对高脂饮食诱导的家兔AS具有显著的干预作用,调节血脂和抑制主动脉氧化应激可能是白杨素抗AS作用机制之一。
关键词: 白杨素 ; 动脉粥样硬化 ; 超氧阴离子 ; 氧化应激

Abstract:

Objective To investigate the effect and mechanism of chrysin on atherosclerosis (AS) induced by high-fat diet in rabbits. Methods Twenty-four male rabbits were randomly divided into three groups: normal control group, model control group, and chrysin group, with 8 rabbits in each group.Rabbits in the model control group and chrysin group were given high fat diet to establish atherosclerosis model.Rabbits in chrysin group were given 25 mg·kg-1 of chrysin, and rabbits in normal control group and model control group were given equal volume of 0.5% of sodium carboxyl methyl cellulose. After 8 weeks of administration, serum lipid levels, aortic pathological changes, aortic superoxide anion (O2·-) levels, and oxidative stress status were observed. Results Compared with model control group, the serum total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) levels in chrysin group were significantly reduced (P<0.05), and high-density lipoprotein cholesterol (HDL-C) level was increased (P<0.05), and the pathological changes of aorta were alleviated, and the aortic O2·- level (P<0.05) and MDA level were significantly decreased (P<0.05), and SOD activity was significantly increased (P<0.05). Conclusion Chrysin has a significant intervention effect on AS induced by high-fat diet in rabbits.Regulation of the blood lipids and inhibition of aortic oxidative stress may be one of the anti-AS mechanisms of chrysin.
Key words: Chrysin ; Atherosclerosis ; Superoxide anion ; Oxidative stress

开放科学(资源服务)标识码(OSID)

动脉粥样硬化(atherosclerosis,AS)诱导的心血管疾病(cardiovascular diseases,CVD)是造成人类死亡的重要原因。据《中国心血管病报告2017》数据显示,我国目前CVD患者约为2.9亿例,同时,我国每年死于CVD约350万例,占总死亡原因41%,居各种疾病之首[1]。目前认为AS是一种脂质沉积于血管壁的慢性炎症疾病[2],在AS病理过程中,除了血管局部的炎症反应和脂质沉积外,氧化应激也在AS发生、发展过程中起到至关重要的作用。

白杨素是一种从紫藏科植物木蝴蝶中提取的天然黄酮类化合物,具有抗癌、抗氧化应激、抑制炎症反应和降低血糖等广泛的药理学作用。体外研究发现,白杨素能显著减轻过氧化氢(H2O2)诱导的人脐静脉内皮细胞氧化应激损伤,抑制细胞间粘附分子-1(intercellular adhesion molecule-1,ICAM-1)和血管间粘附分子-1(vascular adhesion molecule-1,VCAM-1)基因表达,上调细胞一氧化氮(nitric oxide,NO)合成[3]。笔者在本实验拟通过高脂饮食诱导的家兔AS模型观察和分析白杨素在整体水平下对AS的干预作用及机制,为充分挖掘白杨素药理学作用提供一定的理论和实验依据。

1 材料与方法
1.1 实验动物

成年健康雄性日本大耳白兔24只,普通级,体质量(2.8±0.2)kg,购于湖北省实验动物研究中心,实验动物生产许可证号:SCXK(鄂)2015-0018,合格证编号:42000600004459,月龄3~6个月,单独饲养于兔笼内,环境温度20~24 ℃,相对湿度30%~50%,每日12 h明暗周期照明,适应性喂养1周后,开始实验。

1.2 主要试剂及仪器

白杨素,货号:YB-0284,纯度≥90%(上海远慕生物科技有限公司),总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)测试盒(南京建成生物工程研究所),总超氧化物歧化酶(SOD)活性、丙二醛(MDA)、二喹啉甲酸(bicin-choninic acid,BCA)蛋白浓度及苏木精-伊红(HE)染色试剂盒(江苏碧云天生物技术有限公司),RIPA裂解液(江苏碧云天生物技术有限公司),Von Kossa染色试剂盒(武汉赛维尔生物科技有限公司),油红O及二氢乙啡啶(dihydroethidium,DHE,Sigma-Aldrich公司)。

1.3 仪器

H1650离心机(湖南湘仪实验仪器开发有限公司),Allegra 64R低温高速离心机(美国Beckman Coulter公司),1510酶标仪(美国Thermo Fisher公司),BX41多功能显微镜(日本Olympus公司),RM2235石蜡切片机(德国Leica公司),CM1860冰冻切片机(德国Leica公司),BGZ-70电热鼓风干燥箱(上海博迅医疗生物仪器股份有限公司)。

1.4 分组与给药

利用SPSS18.0版统计软件将24只家兔随机分成3组:正常对照组、模型对照组和白杨素组,每组8只。正常对照组给予普通饲料,模型对照组和白杨素组给予高脂饲料(含猪油5%和胆固醇1%)。4周后,白杨素组除给予高脂饲料外,每天灌胃给予白杨素25 mg·kg-1,白杨素采用0.5%羧甲基纤维素钠(CMC-Na)混悬助溶。正常对照组和模型对照组则灌胃给予等体积0.5%CMC-Na混悬液,每天1次,共8周。实验过程中,每周称定体质量1次,按体质量变化调整给药量。

1.5 血脂水平测定

实验结束前一天,禁食12 h,耳缘静脉取血,离心(3500×g,10 min)分离血清,血清TG、TC、LDL-C和HDL-C水平测定严格按照试剂盒说明书步骤执行。

1.6 病理学观察

水合氯醛过量麻醉处死家兔,分离主动脉,4%多聚甲醛固定,脱水、石蜡包埋,切片厚度6 μm,HE和Von Kossa染色步骤严格按染色试剂盒说明书执行。部分主动脉经OCT包埋,冰冻切片机切片,厚度8 μm,进行油红O染色。上述切片在多功能显微镜下进行病理学检查。

1.7 主动脉超氧阴离子(superoxide anion,O2·-)水平测定

主动脉O2·-水平测定通过DHE荧光染色半定量法测定,冰冻切片用磷酸盐缓冲液(PBS)洗3次,每次5 min,DHE(10 μmol)室温避光染色10 min后,PBS清洗切片3次,每次5 min,抗荧光淬灭封片剂封片,多功能显微镜拍照,Image J软件(1.8.0)计算荧光强度。

1.8 主动脉MDA浓度及SOD活性测定

RIPA裂解液冰浴匀浆主动脉,匀浆液在4 ℃条件下离心(12 000×g,5 min),取上清液待测,MDA浓度及SOD活性测定严格按照试剂盒说明进行。此外,用BCA试剂盒测定上清液中蛋白浓度,用于校正MDA浓度及SOD活性。

1.9 统计学方法

采用SPSS18.0版软件进行统计学分析,结果用均数±标准差( x ¯ ±s)表示,采用One-way ANOVA结合Post-Hoc(LSD法)方法进行组间差异分析。以P<0.05表示差异有统计学意义。

2 结果
2.1 白杨素显著改善AS家兔血清脂质紊乱

与正常对照组比较,模型对照组家兔血清TC、TG和LDL-C水平显著升高(P<0.05),HDL-C水平显著降低(P<0.05);与模型对照组比较,白杨素组血清TC、TG和LDL-C水平显著降低(P<0.05),HDL-C水平显著升高(P<0.05)(图1)。


图1 3 组家兔血清脂质指标比较($\bar{x}$±s,n=8)
①与正常对照组比较,P<0.05;②与模型对照组比较,P<0.05。

Fig.1 Comparison of serum lipid among three groups of rabbits($\bar{x}$±s,n=8)
①Compared with normal control group,P<0.05;②Compared with model control group,P<0.05.

2.2 白杨素显著减轻AS家兔主动脉组织病理学变化

HE染色显示:正常对照组家兔主动脉壁的各层结构正常,内膜光滑,中膜弹力纤维在正常状态。模型对照组可见明显内皮部分细胞脱落,内中膜呈明显增厚现象,且凸向管腔内。此外,可见大量的平滑肌细胞移行至内膜下形成纤维帽,内膜下的泡沫细胞及沉积的脂质形成了脂质核心,部分可见钙化。外膜上可见有炎性细胞聚集于此。白杨素组中内膜尚光滑,中膜增厚,泡沫细胞明显减少,未见脂质核心形成(图2)。


图2 3组家兔主动脉组织病理学变化(×100)

Fig.2 Pathological features of aorta in three groups of rabbits(×100)

油红O 染色显示:正常对照组家兔主动脉壁脂质沉积不明显。模型对照组可见明显主动脉壁脂质沉积现象,尤其在内膜层。白杨素组主动脉壁脂质沉积明显减少(图2)。

Von Kossa染色显示:正常对照组小鼠主动脉结构染色均匀,呈淡红色,未见黑色颗粒状沉淀。模型对照组主动脉内膜下可见大量的黑色结节状沉淀,说明存在大量钙化灶。而白杨素组中主动脉内膜下仅见散在的黑色结节,说明存在轻微的动脉钙化灶(图2)。

2.3 白杨素显著降低AS家兔主动脉O2·-水平

DHE染色半定量分析发现,与正常对照组比较,模型对照组主动脉O2·-水平明显升高(P<0.05);与模型对照组比较,白杨素组家兔主动脉O2·-水平显著降低(P<0.05),见图3。


图3 3组家兔主动脉O2·-水平($\bar{x}$±s,n=3)
①与正常对照组比较,P<0.05;②与模型对照组比较,P<0.05。

Fig.3 Aortic O2·- levels in three groups of rabbits($\bar{x}$±s,n=3)
①Compared with normal control group,P<0.05;②Compared with model control group,P<0.05.

2.4 白杨素显著抑制AS家兔主动脉氧化应激

与正常对照组比较,模型对照组家兔主动脉MDA浓度显著升高(P<0.05),SOD活性显著降低(P<0.05);与模型对照组比较,白杨素组家兔主动脉MDA浓度显著降低(P<0.05),SOD活性显著升高(P<0.05),见图4。


图4 3组家兔主动脉MDA含量和SOD活性($\bar{x}$±s,n=3)
①与正常对照组比较,P<0.05;②与模型对照组比较,P<0.05。

Fig.4 Aortic MDA Level and SOD activity in three groups of rabbits($\bar{x}$±s,n=3)
①Compared with normal control group,P<0.05;②Compared with model control group,P<0.05.

3 讨论

AS发病机制复杂,涉及多种风险因素和递质,循环胆固醇水平异常至今仍被认为是AS重要的病理诱因之一,尤其是LDL和HDL[4]。目前认为,升高的血清TG和LDL及降低的HDL具有显著的促AS作用[5]。在促AS饮食喂养的白化Wistar大鼠模型中发现,白杨素能显著降低AS模型大鼠血清TC、TG和LDL-C,升高HDL-C,并显著减轻胸主动脉中膜层损伤和外膜层厚度[6]。笔者在本研究发现,白杨素能显著降低AS家兔血清TC、TG和LDL-C水平,升高HDL-C,减轻AS家兔主动脉组织病理学变化。

氧化应激同样也参与AS发生发展。氧化应激能够导致活性氧物质(reactive oxygen species,ROS)异常增多和抗氧化系统失衡。增多的ROS能够诱导血管内皮细胞功能紊乱,平滑肌细胞增殖和巨噬细胞募集及炎症因子释放等一系列脂质斑块形成的病理事件[7]。O2·-是ROS主要组成物质之一,其降解主要由SOD先催化为过氧化氢,随后通过谷胱甘肽过氧化物酶(glutathione peroxidase,GPx)和过氧化氢酶(catalase,CAT)分解为二氧化碳和水[8]。MDA主要由ROS降解多不饱和脂肪酸产生,其能造成细胞线粒体DNA损伤并加速AS发展[9]。体外实验发现,白杨素能显著抑制还原型烟酰胺腺嘌呤二核苷酸磷酸(nicotinamide adenine dinucleotide phosphate,NADPH)氧化酶诱导血管环O2·-水平[10]。体内实验发现,白杨素能显著提升高胆固醇血症Wistar大鼠血清和肝脏SOD活性,降低肝脏MDA水平[6,11]。本文发现,白杨素能显著降低AS家兔主动脉O2·-和MDA水平,升高主动脉SOD活性,抑制血管局部氧化应激。

本研究也存在部分不足之处:①初步阐明了白杨素可通过抑制血管氧化应激起到抗AS作用,白杨素通过何种机制发挥其抗氧化应激作用尚需进一步研究;②基于动物实验的“3R”原则,本研究中未设置阳性对照组,在下一步阐明白杨素抗AS作用机制的研究中,将设置阳性对照组进一步研究探讨。

本实验发现白杨素能显著改善AS家兔血清脂质异常,减轻主动脉组织病理学变化,降低主动脉O2·-水平,抑制主动脉氧化应激。上述发现表明,白杨素对高脂饮食诱导的AS具有显著的干预作用,调节血脂和抑制主动脉氧化应激可能是其抗AS作用机制之一。

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BACKGROUND: Scutellarin is the major constituent responsible for the clinical benefits of Erigeron breviscapus (Vant.) Hand.-Mazz which finds a long history of ethnopharmacological use in Traditional Chinese Medicine. Scutellarin as a pure compound is now under investigation for its protections against various tissue injuries. PURPOSE: This study aims to examine the effects of scutellarin on oxidative stress-induced vascular endothelial dysfunction and endothelial cell damage, and then to evaluate the therapeutic efficacy of scutellarin in preventing atherosclerosis in rats. METHODS: Radical scavenging ability of scutellarin was determined in vitro. Impact of scutellarin on endothelium-dependent relaxation (EDR) of rabbit thoracic aortic rings upon 1, 1-diphenyl-2-picrylhydrazyl (DPPH) challenge was measured. Influences of scutellarin pre-treatment on the levels of reactive oxygen species (ROS), activities of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase and catalase, and the expression of SOD1 and NADPH oxidase 4 (Nox4) in human umbilical vein endothelial cells (HUVECs) injured by H2O2 were examined. Anti-atherosclerotic effect of scutellarin was evaluated in rats fed with high fat diet (HFD). RESULTS: Scutellarin showed potent antioxidant activity in vitro. Pretreatment of scutellarin retained the EDR of rabbit thoracic aortic rings damaged by DPPH. In H2O2 injured-HUVECs the deleterious alterations in ROS levels and antioxidant enzymes activity were reversed by scutellarin and the mRNA and protein expression of SOD1 and Nox4 were restored also. Oral administration of scutellarin dose-dependently ameliorated hyperlipidemia in HFD-fed rats and alleviated oxidative stress in rat serum, mimicking the effects of reference drug atorvastatin. CONCLUSION: Scutellarin protects against oxidative stress-induced vascular endothelial dysfunction and endothelial cell damage in vitro and prevents atherosclerosis in vivo through antioxidation. The results rationalize further investigation into the clinical use of scutellarin in cardiovascular diseases.
DOI:10.1016/j.phymed.2018.03.021      PMID:29655699      URL    
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[9] ANDREASSI M G,BOTTO N.DNA damage as a new emerging risk factor in atherosclerosis[J].Trends Cardiov Med,2003,13(7):270-275.
DOI:10.1016/S1050-1738(03)00109-9      URL    
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[10] VILLAR I C,VERA R,GALISTEO M,et al.Endothelial nitric oxide production stimulated by the bioflavonoid chrysin in rat isolated aorta[J].Planta medica,2005,71(9):829-834.
In the present study, the effects of the bioflavonoid chrysin (5,7-dihydroxyflavone) were analysed on nitric oxide (NO) production from vascular endothelium. In aortic rings, incubation with chrysin or acetylcholine (both at 10 microM) increased L-NAME-sensitive endothelial NO release as measured using the fluorescent probe 4,5-diaminofluorescein diacetate (DAF-2 DA). Moreover, chrysin increased cGMP accumulation only in aortic rings with endothelium. However, at this concentration, chrysin had no effect either on basal or on NADPH-stimulated vascular superoxide production. Moreover, at this low concentration, chrysin, similar to acetylcholine, induced aortic relaxation, which was abolished by both endothelial deprivation and NO synthase inhibition. Endothelium-dependent relaxation induced by chrysin was unaltered by removal of extracellular calcium and incubation with the intracellular calcium chelator BAPTA, while the phosphatidylinositol (PI)-3 kinase inhibitor wortmannin suppressed the endothelial dependence. In conclusion, chrysin stimulated NO release from endothelial cells leading to vascular cGMP accumulation and subsequent endothelium dependent aortic relaxation. Chrysin-stimulated NO release is calcium independent and possibly mediated via PI3-kinase.
DOI:10.1055/s-2005-871296      PMID:16206037      URL    
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[11] ANANDHI R,ANNADURAI T,ANITHA T S,et al.Antihypercholesterolemic and antioxidative effects of an extract of the oyster mushroom,pleurotus ostreatus,and its major constituent,chrysin,in Triton WR-1339-induced hypercholesterolemic rats[J].J Physiol Biochem,2013,69(2):313-323.

Hypercholesterolemia and oxidative stress are known to accelerate coronary artery disease and progression of atherosclerotic lesions. In the present study, an attempt was made to evaluate the putative antihypercholesterolemic and antioxidative effects of an ethanolic extract of the oyster mushroom (Pleurotus ostreatus) and chrysin, one of its major components, in hypercholesterolemic rats. Hypercholesterolemia was induced in rats by a single intraperitoneal injection of Triton WR-1339 (300 mg/kg body weight (b.wt.)), which resulted in persistently elevated blood/serum levels of glucose, lipid profile parameters (total cholesterol, triglycerides, low-density lipoprotein-, and very low-density lipoprotein-cholesterol), and of hepatic marker enzymes (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase). In addition, lowered mean activities of hepatic antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase) and lowered mean levels of nonenzymatic antioxidants (reduced glutathione, vitamin C, and vitamin E) were observed. Oral administration of the mushroom extract (500 mg/kg b.wt.) and chrysin (200 mg/kg b.wt.) to hypercholesterolemic rats for 7 days resulted in a significant decrease in mean blood/serum levels of glucose, lipid profile parameters, and hepatic marker enzymes and a concomitant increase in enzymatic and nonenzymatic antioxidant parameters. The hypercholesterolemia-ameliorating effect was more pronounced in chrysin-treated rats than in extract-treated rats, being almost as effective as that of the standard lipid-lowering drug, lovastatin (10 mg/kg b.wt.). These results suggest that chrysin, a major component of the oyster mushroom extract, may protect against the hypercholesterolemia and elevated serum hepatic marker enzyme levels induced in rats injected with Triton WR-1339.


DOI:10.1007/s13105-012-0215-6      URL    
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关键词（key words）
白杨素
动脉粥样硬化
超氧阴离子
氧化应激
Chrysin
Atherosclerosis
Superoxide anion
Oxidative stress
作者
杨波
胡有志
张峰
肖金凤
胡勇
YANG Bo
HU Youzhi
ZHANG Feng
XIAO Jinfeng
HU Yong