于熙瀅，周大亮，郭 穎，呂 建，魏 林，曹海利

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依折麥布辛伐他汀片對(duì)兔腹主動(dòng)脈粥樣硬化斑塊逆轉(zhuǎn)作用的實(shí)驗(yàn)研究

于熙瀅1，周大亮1，郭 穎1，呂 建1，魏 林1，曹海利2*

（1哈爾濱市第一醫(yī)院心內(nèi)一科，哈爾濱 150001；2哈爾濱醫(yī)科大學(xué)附屬第二醫(yī)院介入科，哈爾濱 150086）

觀察腹主動(dòng)脈粥樣斑塊內(nèi)炎性巨噬細(xì)胞和平滑肌細(xì)胞的表達(dá)情況，以探索依折麥布聯(lián)合他汀類藥物在逆轉(zhuǎn)動(dòng)脈斑塊中的作用及機(jī)制。選取24只健康雄性新西蘭大耳白兔，隨機(jī)分為對(duì)照組（＝8）和高膽固醇血癥組（＝16）。對(duì)照組給予普通飼料，喂養(yǎng)12周。高膽固醇血癥組喂飼致動(dòng)脈粥樣硬化飼料（由普通顆粒飼料＋15g/L膽固醇＋100g/L豬油＋150g/L蛋黃粉組成）2周后行腹主動(dòng)脈內(nèi)膜球囊拉傷術(shù)，術(shù)后再隨機(jī)分為模型亞組和依折麥布辛伐他汀（ES）亞組（給予5/10mg/（kg·d）每組8只，兩亞組均繼續(xù)喂飼致動(dòng)脈粥樣硬化飼料10周。喂養(yǎng)第12周時(shí)活殺動(dòng)物，取腹主動(dòng)脈進(jìn)行石蠟切片。檢測(cè)不同時(shí)間點(diǎn)脂質(zhì)和脂蛋白，應(yīng)用光學(xué)顯微鏡觀察動(dòng)脈粥樣硬化進(jìn)程，采用免疫組化方法分析巨噬細(xì)胞和平滑肌細(xì)胞在斑塊處的表達(dá)。ES亞組的血清總膽固醇（TC）、甘油三酯（TG）、低密度脂蛋白膽固醇（LDL-C）濃度明顯低于模型亞組（＜0.01）。病理檢測(cè)顯示兩亞組及ES亞組斑塊直徑、斑塊厚度和動(dòng)脈內(nèi)/中膜厚度經(jīng)單因素方差分析，差異有統(tǒng)計(jì)學(xué)意義（＜0.05）。免疫組化檢測(cè)結(jié)果示ES亞組血管壁中巨噬細(xì)胞的表達(dá)量較模型亞組顯著減少（＜0.05），而平滑肌細(xì)胞的表達(dá)量較模型亞組顯著增多（＜0.01）。ES可能通過減少細(xì)胞外脂質(zhì)的沉積，減少內(nèi)膜和中膜巨噬細(xì)胞的數(shù)量和膽固醇的含量，增加膠原和平滑肌細(xì)胞面積，從而起到逆轉(zhuǎn)斑塊的作用。

兔；主動(dòng)脈，腹；巨噬細(xì)胞；肌細(xì)胞，平滑肌；依折麥布辛伐他汀片

在動(dòng)脈粥樣硬化的發(fā)生發(fā)展過程中，膽固醇逆向轉(zhuǎn)運(yùn)的紊亂，血管壁巨噬細(xì)胞黏附，平滑肌細(xì)胞移行增殖并蓄積脂質(zhì)形成泡沫細(xì)胞是一個(gè)重要的環(huán)節(jié)[1?5]。能有效抑制這一環(huán)節(jié)并促進(jìn)細(xì)胞內(nèi)膽固醇逆向轉(zhuǎn)運(yùn)的藥物研發(fā)一直是動(dòng)脈粥樣硬化研究關(guān)注的熱點(diǎn)。依折麥布辛伐他汀（ES）片作為一種新型選擇性膽固醇吸收抑制劑與他汀類藥物的合劑，在臨床應(yīng)用中因其可有效彌補(bǔ)單獨(dú)應(yīng)用他汀類藥物的不足而倍受青睞[3,6?9]。但ES片明顯降低低密度脂蛋白膽固醇（low density lipoprotein cholesterol，LDL-C）水平能否逆轉(zhuǎn)動(dòng)脈粥樣硬化的進(jìn)程仍未有定論。本研究擬通過建立家兔動(dòng)脈粥樣硬化模型，觀察腹主動(dòng)脈粥樣斑塊內(nèi)炎性巨噬細(xì)胞和平滑肌細(xì)胞的表達(dá)情況，從而探索依折麥布聯(lián)合他汀類藥物在逆轉(zhuǎn)動(dòng)脈斑塊中的作用及機(jī)制。

1 材料與方法

1.1 動(dòng)物模型的建立及分組

雄性新西蘭大白兔24只，體質(zhì)量2.0～2.5kg。將兔單籠喂養(yǎng)普通飼料1周。24只兔隨機(jī)分為對(duì)照組（8只）和高膽固醇血癥組（16只）。對(duì)照組給予普通飼料。高膽固醇血癥組供給致動(dòng)脈粥樣硬化飼料（由普通顆粒飼料＋15g/L膽固醇＋100g/L豬油＋150g/L蛋黃粉組成）。喂養(yǎng)2周后，參照文獻(xiàn)[10]的方法進(jìn)行腹主動(dòng)脈內(nèi)膜球囊損傷術(shù)。術(shù)后再隨機(jī)分為模型亞組（＝8）和ES亞組（＝8）。模型亞組繼續(xù)喂飼致動(dòng)脈粥樣硬化飼料10周。ES亞組除喂飼致動(dòng)脈粥樣硬化飼料加用ES片5/10mg/（kg·d）。喂養(yǎng)第12周時(shí)進(jìn)行腹主動(dòng)脈造影。并留取腹主動(dòng)脈左腎動(dòng)脈水平以下5cm的血管作為標(biāo)本。所有動(dòng)物均于實(shí)驗(yàn)開始和結(jié)束前空腹取每只兔耳緣靜脈血測(cè)定血清總膽固醇（total cholesterol，TC）、甘油三酯（triglycerides，TG）和高密度脂蛋白膽固醇、LDL-C，進(jìn)行血液學(xué)檢查。

1.2 實(shí)驗(yàn)材料及試劑

依折麥布辛伐他汀片（固定劑量復(fù)方制劑，商品名：葆至能，規(guī)格：依折麥布10mg/辛伐他汀20mg，由默沙東?先靈葆雅公司生產(chǎn)，注冊(cè)證號(hào)H20090344）。鼠抗兔巨噬細(xì)胞單克隆抗體（RAM11，丹麥DAKO公司），SP免疫組化染色試劑盒（北京中杉金橋生物技術(shù)有限公司），膽固醇（武漢亞法生物技術(shù)拓展公司進(jìn)口分裝），TC、TG試劑盒（英國(guó)Randow公司），LDL-C生化試劑盒（日本第一化學(xué)公司）。

1.3 給藥劑量、途徑及時(shí)間

由于辛伐他汀在水中溶解度較差但易溶于乙醇。取適量藥品溶解于乙醇，一邊添加一邊攪拌，并在渦旋儀上震蕩2min。并在給藥時(shí)注意充分使藥物混懸液分布均勻。本實(shí)驗(yàn)根據(jù)相關(guān)參考文獻(xiàn)[11]以及人與各種動(dòng)物的劑量折算系數(shù)法，并在安全許可劑量范圍內(nèi)我們?cè)O(shè)計(jì)應(yīng)用ES片5/10mg/（kg·d）劑量。兔經(jīng)口灌胃，每天傍晚（17∶00～18∶00）給藥1次，每次給藥體積控制在5～7ml。

1.4 實(shí)驗(yàn)方法

1.4.1 藥物觸發(fā) 3組白兔均給予中國(guó)斑點(diǎn)蝰蛇毒0.15mg/kg腹膜下注射，30min后，經(jīng)耳緣靜脈注射組胺0.02mg/kg，于活殺動(dòng)物前24和48h給予兩次藥物觸發(fā)斑塊破裂。

1.4.2 腹主動(dòng)脈造影檢查 對(duì)照組、模型亞組、ES亞組3組動(dòng)物分別于12周行腹主動(dòng)脈造影檢查，手術(shù)切開暴露右股動(dòng)脈，穿刺針直視下穿刺，留置管鞘，行腹主動(dòng)脈造影。以Image-Pro Plus6.0軟件精確測(cè)量每根腹主動(dòng)脈狹窄區(qū)的最小殘腔直徑（diameter of minimum cavity，DMC）和狹窄遠(yuǎn)端腹主動(dòng)脈直徑（diameter of distal abdominal，DDA）。狹窄率＝（DDA－DMC）/DDA×100%。狹窄程度的判定標(biāo)準(zhǔn)：狹窄率＜30%為輕度狹窄，30%～69%為中度狹窄，70%～99%為重度狹窄，100%為完全閉塞。

1.5 病理標(biāo)本的留取

1.5.1 標(biāo)本大體形態(tài)觀察 動(dòng)物活殺后取出腹主動(dòng)脈全長(zhǎng)，縱行切開，生理鹽水沖洗干凈后，觀察斑塊形成情況。然后以4%甲醛固定，同時(shí)用HE染色整條主動(dòng)脈，進(jìn)行病理切片后經(jīng)Image-Pro Plus6.0分析系統(tǒng)處理，計(jì)算斑塊直徑、斑塊厚度、內(nèi)/中膜厚度。

1.5.2 免疫組織化學(xué)檢查 選取鄰近主動(dòng)脈弓部的降主動(dòng)脈，置于4%甲醛固定48h，常規(guī)石蠟包埋，血管橫斷面作4μm連續(xù)切片，分別做HE染色及巨噬細(xì)胞和平滑肌肌動(dòng)蛋白的免疫化學(xué)染色。應(yīng)用RAM11抗體和α-肌動(dòng)蛋白（actin）抗體分別測(cè)定斑塊破裂與未破裂部位的巨噬細(xì)胞和平滑肌肌動(dòng)蛋白的局部表達(dá)。

1.6 統(tǒng)計(jì)學(xué)處理

2 結(jié) 果

2.1 各組兔血脂變化情況

在喂養(yǎng)過程中，模型亞組死亡2只，ES亞組死亡1只。實(shí)驗(yàn)前各組兔血清TC、TG、LDL-C比較，差異無統(tǒng)計(jì)學(xué)意義（＞0.05）。與實(shí)驗(yàn)前比較，對(duì)照組12周后TC、TG、LDL-C無明顯變化（＞0.05），而兩亞組12周后血清TC、TG、LDL-C較實(shí)驗(yàn)前明顯升高（＜0.01），并且高于對(duì)照組（＜0.01），ES亞組血清TC、TG、LDL-C較模型亞組明顯下降（＜0.01；表1）。

2.2 腹主動(dòng)脈狹窄程度

對(duì)照組無狹窄。兩亞組均有不同程度的狹窄，模型亞組多為中重度狹窄，無完全閉塞者。ES亞組多為輕度狹窄。

2.3 病理形態(tài)學(xué)觀察

對(duì)照組兔的動(dòng)脈內(nèi)皮細(xì)胞完整，無明顯脂質(zhì)沉積（圖1A）。模型亞組部分斑塊中有新生血管，并有大量的炎癥細(xì)胞浸潤(rùn)，多數(shù)血管可見粥樣斑塊或纖維斑塊，內(nèi)膜下大量胞漿淡染和充滿脂質(zhì)空泡的泡沫細(xì)胞，彈力纖維崩解、斷裂、溶解，斑塊纖維帽薄，膠原少，呈典型的易損斑塊（圖1B）。ES亞組動(dòng)脈壁內(nèi)膜厚度明顯小于模型亞組，內(nèi)膜完整，泡沫細(xì)胞減少，脂質(zhì)沉積少（圖1C）。

2.4 斑塊直徑、厚度及內(nèi)/中膜厚度

病理檢測(cè)顯示兩亞組12周時(shí)斑塊直徑、斑塊厚度、內(nèi)/中膜厚度，經(jīng)單因素方差分析表明，差異有統(tǒng)計(jì)學(xué)意義（＜0.01；表2）。

2.5 免疫組織化學(xué)分析

經(jīng)Image-Pro Plus6.0分析系統(tǒng)處理，對(duì)照組缺乏巨噬細(xì)胞表達(dá)，可見中層平滑肌細(xì)胞著色，無內(nèi)膜增生（圖2A，3A）。以斑塊纖維帽500μm×100μm的面積區(qū)域計(jì)數(shù)細(xì)胞數(shù)。結(jié)果顯示與ES亞組相比，模型亞組巨噬細(xì)胞的數(shù)量較之明顯增多（46.4±5.638.6±6.4），差異具有統(tǒng)計(jì)學(xué)意義（＜0.05；圖2B，2C）；模型亞組平滑肌細(xì)胞較ES亞組明顯減少（57.6±6.371.2±4.9），差異有統(tǒng)計(jì)學(xué)意義（＜0.01；圖3B，3C）。

3 討 論

動(dòng)脈粥樣硬化的典型病理學(xué)特征是動(dòng)脈壁內(nèi)皮下間隙脂質(zhì)沉積、內(nèi)膜增厚乃至最終出現(xiàn)血管腔的狹窄。許多證據(jù)表明，單核巨噬細(xì)胞的黏附和平滑肌細(xì)胞的內(nèi)膜遷移在動(dòng)脈粥樣硬化的發(fā)生發(fā)展中具有重要作用[12?15]。如何有效地抑制甚或逆轉(zhuǎn)泡沫細(xì)胞（巨噬細(xì)胞、平滑肌細(xì)胞吞噬脂質(zhì)成為泡沫細(xì)胞）的形成成為防治動(dòng)脈粥樣硬化的關(guān)鍵。實(shí)驗(yàn)研究已證實(shí)，高脂血癥可引起單核巨噬細(xì)胞發(fā)生功能改變?cè)鲞M(jìn)黏附進(jìn)入動(dòng)脈內(nèi)膜的能力，同時(shí)又能促進(jìn)平滑肌細(xì)胞向內(nèi)膜移動(dòng)。本研究顯示，動(dòng)脈粥樣斑塊中巨噬細(xì)胞明顯增多，模型亞組巨噬細(xì)胞表達(dá)較ES亞組顯著增多，說明炎癥反應(yīng)促成了腹主動(dòng)脈粥樣硬化的形成，并可能進(jìn)一步導(dǎo)致斑塊的不穩(wěn)定。

表1 兔實(shí)驗(yàn)前后血脂水平

TC: total cholesterol; TG: triglycerides; LDL-C: low density lipoprotein cholesterol; ES: ezetimibe/simvastatin. Compared with control group,**＜0.01; compared with model subgroup,##＜0.01; compared with the beginning of the experiment in the same group,△△＜0.01

圖1 兔腹主動(dòng)脈HE染色結(jié)果

Figure 1 Hematoxylin-eosin staining results of rabbits abdominal aorta (×40) A: control group; B: model subgroup; C: ES subgroup

圖2 巨噬細(xì)胞免疫組化染色結(jié)果

Figure 2 Results of immunohistochemical staining in macrophages(×400) A: control group; B: model subgroup; C: ES subgroup

圖3 平滑肌肌動(dòng)蛋白免疫組化染色結(jié)果

Figure 3 Results of immunohistochemical staining in smooth muscle actin (×400) A: control group; B: model subgroup; C: ES subgroup

表2 兩亞組斑塊直徑、厚度、內(nèi)-中膜厚度比較

Compared with model subgroup,**＜0.01

依折麥布是一種選擇性膽固醇吸收抑制劑，其作用機(jī)制主要是阻斷膽固醇的外源性吸收途徑。其口服后被迅速吸收且廣泛結(jié)合成依折麥布－葡萄糖苷酸，作用于小腸細(xì)胞的刷狀緣，通過抑制C型1類尼曼匹克?C1樣蛋白l（Niemann-Pick C1 like 1，NPC1L1），選擇性地抑制膳食和膽汁中的膽固醇跨小腸壁轉(zhuǎn)運(yùn)，有效地阻止膽固醇和植物固醇的吸收。一項(xiàng)單藥治療的研究[16]顯示，10mg依折麥布單藥治療2周后，LDL-C較基線水平降低了20.4%，安慰劑組則升高了1.9%；組間相比，LDL-C降幅相差22.3%。辛伐他汀作為一種羥甲基戊二酰輔酶A還原酶抑制劑，能特異性地降低肝細(xì)胞中膽固醇的合成，進(jìn)而發(fā)揮降低血脂的作用。兩者聯(lián)合應(yīng)用可分別從膽固醇的內(nèi)、外源性途徑對(duì)血脂水平進(jìn)行調(diào)節(jié)以達(dá)到最佳調(diào)脂效果[17]。本研究動(dòng)物實(shí)驗(yàn)顯示，連續(xù)12周5/10mg/（kg·d）的ES片可有效減輕新西蘭兔主動(dòng)脈粥樣硬化的病變程度，內(nèi)/中膜變薄，內(nèi)皮下間隙脂質(zhì)以及壞死物質(zhì)減少，血管壁結(jié)構(gòu)得到了有效的改善。本研究中ES亞組顯著降低高膽固醇血癥家兔血清TC、TG和LDL-C濃度，同時(shí)，還顯著抑制了腹主動(dòng)脈粥樣斑塊的形成，該亞組斑塊近心端巨噬細(xì)胞和表達(dá)的數(shù)目較模型組明顯減少，減輕了斑塊近心端細(xì)胞外基質(zhì)的降解，使斑塊趨向穩(wěn)定。

本研究的局限性在于樣本量較小，且觀察時(shí)間較短。只設(shè)有ES片兩者組成的固定復(fù)方制劑ES組，未設(shè)有與依折麥布單藥及辛伐他汀單藥組的療效對(duì)照研究。在后續(xù)研究中，將擴(kuò)大樣本量，延長(zhǎng)觀察時(shí)間，通過與單藥治療對(duì)比以觀察ES片對(duì)遠(yuǎn)期心臟事件的影響?？傊?，ES片的治療可穩(wěn)定動(dòng)脈粥樣硬化斑塊，包括可減少細(xì)胞外脂質(zhì)的沉積，減少內(nèi)膜和中膜巨噬細(xì)胞的數(shù)量和膽固醇的含量，增加膠原和平滑肌細(xì)胞面積，減少內(nèi)膜的鈣化和新生血管，通過減少血中LDL-C水平，縮小斑塊內(nèi)脂核，減少斑塊表面張力，加固斑塊纖維帽，最大限度地穩(wěn)定斑塊并使其退縮，具有較強(qiáng)的抗增殖作用和抗遷移作用。

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（編輯: 周宇紅）

Effects of ezetimibe/simvastatin tablets on atherosclerotic plaque regression of abdominal arteries in rabbits

YU Xi-Ying1, ZHOU Da-Liang1, GUO-Ying1, LYU- Jian1, WEI-Lin1, CAO Hai-Li2*

(1Department No.1 of Cardiology, Harbin First Hospital, Harbin 150010, China;2Department of Interventional Radiology, the Second Affiliated Hospital, Harbin Medical University, Harbin 150086, China)

To observe the efficiency of ezetimibe/simvastatin (ES) tablets on the regression of atherosclerotic plaque of abdominal arteries in rabbits.Twenty-four healthy male New Zealand rabbits were randomly divided into 2 groups: control group (＝8) and hypercholesterolemia group (＝16). Control group was fed with normal diet for 12 weeks. The other group animals were given a cholesterol-supplemented diet (normal diet＋15g/Lcholesterol＋100g/Llard＋150g/Legg yolk powder) for 2 weeks, and underwent catheter-induced arterial wall injury. These rabbits were then randomized to model subgroup (＝8, for another 10 weeks of hypercholesterol diet) and ES treatment subgroup [＝8, 5/10mg/(kg·d) for another 10 weeks]. Chinese russell’s viper venom was intra-peritoneally injected to trigger plaque rupture. Abdominal aortagraphy was carried out to measure the aorta stenosis. After 12 weeks’ feeding, all rabbits were sacrificed, and their abdominal arteries were isolated, paraffin-embedded and then sectioned. Blood lipid and lipoproteins were detected. The development of the atherosclerotic plaques was evaluated through the light microscopy. Finally, the expression of macrophage and smooth muscle actin in the abdominal arteries was measured by immunohistochemical analysis.The serum levels of total cholesterol (TC), triglycerides (TG) and low density lipoprotein-cholesterol (LDL-C) were significantly lower in the ES treatment subgroup than in the hypercholesterolemia model group (＜0.01). One-way analysis of variance indicated that significant differences were found in the plaque diameter, plaque thickness and the intimal-medial thickness between the ES subgroup and hypercholesterolemia model subgroup by morphological observation (＜0.05). Immunohistochemical analysis showed that lesser macrophages (＜0.05) but more smooth muscle cells (＜0.01) were found in the ES treatment subgroup than in the model group.It may be through reducing the deposition of extracellular lipids that ES treatment decreases macrophage number and cholesterol level, increases the collagen and smooth muscle cells in the arterial intima and media, and thus exerts effect on plaque reversing.

rabbits; aorta, abdominal; macrophage; myocyte, smooth muscle; ezetimibe/simvastatin tablets

R543.1+2

A

10.3724/SP.J.1264.2014.000214

2014?08?24;

2014?10?21

曹海利, E-mail: 18746013637@163.com