金鉉順，李夢京，金 石，張國杰，元奎昌

·論著·

原花青素對多囊卵巢綜合征合并動脈粥樣硬化模型大鼠的作用

金鉉順，李夢京，金 石，張國杰，元奎昌*

目的 探究原花青素對多囊卵巢綜合征(PCOS)合并動脈粥樣硬化模型大鼠的作用及其機制。方法 2015年1—10月，采用隨機數(shù)字表法從20只健康雌性清潔級SD大鼠中選取15只為建模組，在其頸背部皮下埋置雙氫睪酮(DHT)緩釋片，并且定期更換DHT緩釋片的同時，給予高脂飼料配方，給予充分的顆粒飼料和水，建立PCOS合并動脈粥樣硬化模型大鼠；其余5只大鼠為對照組，常規(guī)飼養(yǎng)。16周后，分別檢測兩組大鼠體質量、雄激素、瘦素、胰島素水平，光學顯微鏡下觀察其主動脈內膜病理情況，以驗證PCOS合并動脈粥樣硬化模型大鼠成功與否。將建模成功的15只大鼠采用隨機數(shù)字表法分為模型組、辛伐他汀組、原花青素組，各5只。對照組與模型組大鼠給予0.9%氯化鈉溶液，辛伐他汀組大鼠給予辛伐他汀片，原花青素組大鼠給予原花青素。治療4周后，檢測4組大鼠脂代謝指標〔總膽固醇(TC)、三酰甘油(TG)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)〕水平、脂代謝關鍵基因〔過氧化物酶體增殖物激活受體γ(PPAR-γ)、3-羥基-3-甲基戊二酰輔酶A還原酶(HMG-CoA還原酶)、ATP結合盒轉運子A1(ABCA1)、肝臟X受體α(LXR-α)、法尼醇受體(FXR)〕mRNA表達水平。結果 建模組體質量、雄激素、瘦素、胰島素水平均低于對照組(P<0.05)。光學顯微鏡下觀察大鼠主動脈內膜病理情況，結果顯示，與對照組相比，建模組大鼠主動脈內膜出現(xiàn)大量粥樣斑塊及膽固醇結晶。模型組TC、TG、LDL水平高于對照組(P<0.05)；辛伐他汀組TC、TG、LDL水平低于模型組，HDL水平高于對照組、模型組(P<0.05)；原花青素組TC、TG、LDL水平低于模型組，TC、LDL水平低于辛伐他汀組，HDL水平高于對照組、模型組(P<0.05)。模型組PPAR-γ、HMG-CoA還原酶、FXR mRNA表達水平低于對照組(P<0.05)；辛伐他汀組PPAR-γ、HMG-CoA還原酶、ABCA1、LXR-α、FXR mRNA表達水平高于模型組，HMG-CoA還原酶、ABCA1、LXR-α、FXR mRNA表達水平高于對照組(P<0.05)；原花青素組PPAR-γ、HMG-CoA還原酶、ABCA1、LXR-α、FXR mRNA表達水平高于對照組、模型組，HMG-CoA還原酶mRNA表達水平高于辛伐他汀組(P<0.05)。4組大鼠主動脈內膜病理情況：與對照組相比，模型組大鼠主動脈內膜出現(xiàn)大量粥樣斑塊及膽固醇結晶；與模型組相比，辛伐他汀組大鼠主動脈內膜粥樣斑塊縮小，同時膽固醇結晶也減少；與辛伐他汀組相比，原花青素組大鼠主動脈內膜粥樣斑塊縮小更多，同時膽固醇結晶也減少更多。結論 原花青素可改善PCOS合并動脈粥樣硬化模型大鼠脂代謝水平并縮減動脈粥樣斑塊。

多囊卵巢綜合征；動脈粥樣硬化；原花青素類；大鼠；辛伐他汀

金鉉順,李夢京,金石,等.原花青素對多囊卵巢綜合征合并動脈粥樣硬化模型大鼠的作用[J].中國全科醫(yī)學，2017，20(12)：1463-1468.[www.chinagp.net]

JIN X S,LI M J,JIN S,et al.Effect of procyanidine on rat models of polycystic ovary syndrome complicated with atherosclerosis[J].Chinese General Practice，2017，20(12)：1463-1468.

多囊卵巢綜合征(polycystic ovary syndrome，PCOS)是女性常見的一類內分泌疾病[1]，以高雄激素血癥及長期不排卵為主要特征，同時可伴有痤瘡、月經(jīng)量少、肥胖、代謝紊亂及心血管系統(tǒng)功能紊亂等臨床表現(xiàn)[2-3]。研究統(tǒng)計，PCOS影響著全世界約7%女性的健康[3]。內分泌紊亂是引起機體代謝失調的前提。多項研究表明，大多數(shù)PCOS患者存在代謝綜合征，其表現(xiàn)如高血壓、脂代謝異常、肥胖、胰島素抵抗[4]。同時，PCOS患者心血管疾病患病率明顯增加，成為影響患者預后的主要因素[4-6]。但PCOS與代謝紊亂是否與心血管疾病相關，尚未見明確報道。研究顯示，80%以上的PCOS患者患有心血管疾病，特別是動脈粥樣硬化[7]。原花青素是存在于多種植物，如葡萄、藍莓、紫薯、櫻桃等中的一類含多酚羥基的黃酮類化合物[8-9]。研究顯示，合理攝入原花青素可起到抗氧化、抑制腫瘤及抗感染等多種作用[10-11]。在動脈粥樣硬化的發(fā)生與發(fā)展過程中，體內氧化應激增強所致脂質過氧化、泡沫細胞的激活以及機體脂質代謝異常，是引起動脈粥樣斑塊形成的重要因素[12-15]。ZHANG等[16]通過對比動脈粥樣硬化患者服用原花青素前后動脈粥樣斑塊大小、動脈內膜厚度等指標發(fā)現(xiàn)，原花青素可明顯減小動脈粥樣斑塊，提示原花青素具有抗動脈粥樣硬化的療效。因此，結合原花青素抗氧化的特性以及脂質代謝異常在動脈粥樣硬化中扮演的重要角色，本研究觀察原花青素對PCOS合并動脈粥樣硬化模型大鼠的作用及其機制，以期為探究PCOS病因及其多項并發(fā)癥的病因提供理論指導。

1 材料與方法

1.1 實驗動物 2015年1—10月，選取健康雌性清潔級SD大鼠20只，體質量(170±20)g，4周齡，由延邊大學實驗動物中心提供(合格證號為醫(yī)動字第220010016號)。飼養(yǎng)環(huán)境：相對濕度50%～70%，溫度20～25 ℃，飼料由延邊大學實驗動物中心提供(執(zhí)行標準GB149241994)，動物實驗房的合格號為醫(yī)動字第220010015號。

1.2 藥品與儀器 原花青素購于默沙東(中國)有限公司；辛伐他汀片購于杭州康泰藥業(yè)有限公司；雄激素、瘦素、胰島素、總膽固醇(TC)、三酰甘油(TG)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)檢測試劑盒購于上海碧云天生物技術有限公司；DM2500型光學顯微鏡、DFA450攝像頭購于上海日立電器有限公司。

1.3 研究方法

1.3.1 PCOS合并動脈粥樣硬化模型大鼠的建立 采用隨機數(shù)字表法選取15只大鼠為建模組，在其頸背部皮下埋置雙氫睪酮(DHT)緩釋片(5 mg/90 d，美國Innovative Research公司，美國密西西比州Reckelhoff JF生理實驗室贈予)，并且在定期更換DHT緩釋片的同時，給予高脂飼料配方(4%膽固醇+6%花生油+90%基礎飼料，由沈陽市于洪區(qū)前民動物實驗飼料廠加工成顆粒飼料)，給予充分的顆粒飼料和水。其余5只大鼠為對照組，常規(guī)飼養(yǎng)。16周后，分別檢測兩組大鼠體質量，按照檢測試劑盒說明書檢測雄激素、瘦素、胰島素水平，DM2500型光學顯微鏡下觀察其主動脈內膜病理情況，以驗證PCOS合并動脈粥樣硬化模型大鼠成功與否。

1.3.2 治療方法 將建模成功的15只大鼠采用隨機數(shù)字表法分為模型組、辛伐他汀組、原花青素組，各5只。對照組與模型組大鼠灌胃給予10 ml/kg 0.9%氯化鈉溶液，1次/d；辛伐他汀組大鼠灌胃給予4 mg/kg辛伐他汀片，1次/d；原花青素組大鼠灌胃給予50 mg/kg原花青素，1次/d。

1.3.3 檢測脂代謝指標(TC、TG、LDL、HDL)水平 治療4周后，抽取4組大鼠尾靜脈血，分離血漿，采用試劑盒檢測血漿TC、TG、LDL、HDL水平。

1.3.4 檢測脂代謝關鍵基因〔過氧化物酶體增殖物激活受體γ(PPAR-γ)、3-羥基-3-甲基戊二酰輔酶A還原酶(HMG-CoA還原酶)、ATP結合盒轉運子A1(ABCA1)、肝臟X受體α(LXR-α)、法尼醇受體(FXR)〕mRNA表達水平 治療4周后，斷頸處死各組大鼠，收集頸動脈血后分離血漿，采用實時熒光定量PCR法檢測脂代謝關鍵基因(PPAR-γ、HMG-CoA還原酶、ABCA1、LXR-α、FXR)mRNA表達水平。PCR反應條件：95 ℃預變性10 min；95 ℃變性15 s，60 ℃退火30 s，72 ℃延伸30 s，共40個循環(huán)；72 ℃末次延伸5 min。以GAPDH為內參，采用2-ΔΔCT法計算目的基因mRNA表達水平。

1.3.5 觀察大鼠主動脈內膜病理情況 采用DM2500型光學顯微鏡、DFA450攝像頭觀察大鼠主動脈內膜病理情況。

2 結果

2.1 PCOS合并動脈粥樣硬化大鼠模型的鑒定 建模組體質量、雄激素、瘦素、胰島素水平均低于對照組，差異有統(tǒng)計學意義(P<0.05，見表1)。光學顯微鏡下觀察大鼠主動脈內膜病理情況，結果顯示，與對照組相比，建模組大鼠主動脈內膜出現(xiàn)大量粥樣斑塊及膽固醇結晶(見圖1)。

Table 1 Comparison of general data between control group and modeling group

組別只數(shù)體質量(g)雄激素(ng/ml)瘦素(ng/ml)胰島素(mU/L)對照組5196±173.7±0.43.98±0.0129.4±0.9建模組15176±211.8±0.62.14±0.4618.2±0.3t值1.9196.55015.48127.325P值0.071<0.001<0.001<0.001

圖1 光學顯微鏡下觀察對照組、建模組主動脈內膜病理情況(HE染色，×400)

Figure 1 Pathological conditions of the aortic tunica intima in control group and modeling group observed by optical microscopy

2.2 對照組、模型組、辛伐他汀組、原花青素組脂代謝指標水平比較 對照組、模型組、辛伐他汀組、原花青素組TC、TG、LDL、HDL水平比較，差異有統(tǒng)計學意義(P<0.05)。其中模型組TC、TG、LDL水平高于對照組，差異有統(tǒng)計學意義(P<0.05)；辛伐他汀組TC、TG、LDL水平低于模型組，HDL水平高于對照組、模型組，差異有統(tǒng)計學意義(P<0.05)；原花青素組TC、TG、LDL水平低于模型組，TC、LDL水平低于辛伐他汀組，HDL水平高于對照組、模型組，差異有統(tǒng)計學意義(P<0.05，見表2)。

Table 2 Comparison of levels of indicators of lipid metabolism in control group,model subgroup,simvastatin subgroup and procyanidine subgroup

組別只數(shù)TCTGLDLHDL對照組51.52±0.341.24±0.081.16±0.131.23±0.18模型組53.44±0.14a2.98±0.07a2.96±0.32a1.01±0.25辛伐他汀組51.81±0.33b1.62±0.72b1.31±0.32b1.98±0.43ab原花青素組51.13±0.42bc1.02±0.62b0.92±0.23bc2.23±0.51abF值48.52516.68263.48912.824P值<0.001<0.001<0.001<0.001

注：TC=總膽固醇，TG=三酰甘油， LDL=低密度脂蛋白，HDL=高密度脂蛋白；與對照組比較，aP<0.05；與模型組比較，bP<0.05；與辛伐他汀組比較，cP<0.05

2.3 對照組、模型組、辛伐他汀組、原花青素組脂代謝關鍵基因mRNA表達水平比較 對照組、模型組、辛伐他汀組、原花青素組PPAR-γ、HMG-CoA還原酶、ABCA1、LXR-α、FXR mRNA表達水平比較，差異有統(tǒng)計學意義(P<0.05)。其中模型組PPAR-γ、HMG-CoA還原酶、FXR mRNA表達水平低于對照組，差異有統(tǒng)計學意義(P<0.05)；辛伐他汀組PPAR-γ、HMG-CoA還原酶、ABCA1、LXR-α、FXR mRNA表達水平高于模型組，HMG-CoA還原酶、ABCA1、LXR-α、FXR mRNA表達水平高于對照組，差異有統(tǒng)計學意義(P<0.05)；原花青素組PPAR-γ、HMG-CoA還原酶、ABCA1、LXR-α、FXR mRNA表達水平高于對照組、模型組，HMG-CoA還原酶mRNA表達水平高于辛伐他汀組，差異有統(tǒng)計學意義(P<0.05，見表3)。

2.4 對照組、模型組、辛伐他汀組、原花青素組大鼠主動脈內膜病理情況 與對照組相比，模型組大鼠主動脈內膜出現(xiàn)大量粥樣斑塊及膽固醇結晶；與模型組相比，辛伐他汀組大鼠主動脈內膜粥樣斑塊縮小，同時膽固醇結晶也減少；與辛伐他汀組相比，原花青素組大鼠主動脈內膜粥樣斑塊縮小更多，同時膽固醇結晶也減少更多(見圖2)。

Table 3 Comparison of mRNA expressions of lipid metabolism-associated genes in control group,model subgroup,simvastatin subgroup and procyanidine subgroup

組別只數(shù)PPAR-γmRNAHMG-CoA還原酶mRNAABCA1mRNALXR-αmRNAFXRmRNA對照組512.3±3.38.5±1.34.5±1.29.1±2.28.2±1.4模型組55.0±0.8a3.6±0.8a2.5±0.55.5±1.14.2±0.8a辛伐他汀組516.3±4.3b18.5±3.3ab13.9±3.2ab18.3±3.7ab15.3±3.6ab原花青素組518.5±5.3ab27.5±6.1abc17.6±4.4ab22.2±4.9ab17.4±4.2abF值12.04244.75033.61627.68523.098P值<0.001<0.001<0.001<0.001<0.001

注：PPAR-γ=過氧化物酶體增殖物激活受體γ，HMG-CoA還原酶=3-羥基-3-甲基戊二酰輔酶A還原酶，ABCA1=ATP結合盒轉運子A1，LXR-α=肝臟X受體α，F(xiàn)XR=法尼醇受體；與對照組比較，aP<0.05；與模型組比較，bP<0.05；與辛伐他汀組比較，cP<0.05

圖2 光學顯微鏡下觀察對照組、模型組、辛伐他汀組、原花青素組主動脈內膜病理情況(HE染色，×400)

Figure 2 Pathological conditions of the aortic tunica intima in control group,model subgroup,simvastatin subgroup and procyanidine subgroup observed by optical microscopy

3 討論

PCOS是起源于青春期的生殖內分泌紊亂疾病，也是育齡期婦女最常見的內分泌疾病，患病率達5%～10%，在無排卵性不育的婦女中為50%～60%[17]。PCOS臨床表現(xiàn)多樣，以高雄激素血癥和長期無排卵為主要特征，多表現(xiàn)為肥胖、不孕和卵巢囊性增大，且PCOS易引發(fā)多種并發(fā)癥，尤其是心血管疾病，80%以上的PCOS患者患有心血管疾病，特別是動脈粥樣硬化[18]。PCOS患者伴有動脈粥樣硬化的可能機制如下[19]：(1)游離脂肪酸的抑制作用減弱，導致LDL和TG合成增加，同時脂蛋白酯酶和肝脂酶的活性降低，肝臟對LDL和TG的清除率降低。(2)脂質沉積代謝異常，導致脂蛋白酯酶活性受到抑制，從而增加了TG水平，降低了HDL水平，PCOS伴肥胖使血中雄激素、瘦素、胰島素抵抗(IR)水平增加，在其協(xié)同作用下進一步加重代謝紊亂。

原花青素是存在于多種植物內的一類含多酚羥基的黃酮類化合物。研究顯示，原花青素具有抗動脈粥樣硬化的作用[20]。因此，結合原花青素抗氧化的特性以及脂質代謝異常在動脈粥樣硬化中扮演的重要角色，本研究觀察原花青素對PCOS合并動脈粥樣硬化模型大鼠的作用及其機制，結果顯示，建模組體質量、雄激素、瘦素、胰島素水平均低于對照組；光學顯微鏡下觀察大鼠主動脈內膜病理情況，結果顯示，與對照組相比，建模組大鼠主動脈內膜出現(xiàn)大量粥樣斑塊及膽固醇結晶。說明PCOS合并動脈粥樣硬化模型大鼠建模成功。TC、TG、LDL和HDL是評價動脈粥樣硬化的常見指標，TC、TG、LDL水平越高，HDL水平越低，表明動脈粥樣硬化程度越嚴重[18]。模型組TC、TG、LDL水平高于對照組；辛伐他汀組TC、TG、LDL水平低于模型組，HDL水平高于對照組、模型組；原花青素組TC、TG、LDL水平低于模型組，TC、LDL水平低于辛伐他汀組，HDL水平高于對照組、模型組。PPAR-γ、HMG-CoA還原酶、ABCA1、LXR-α、FXR為大鼠脂代謝關鍵基因，其mRNA能夠啟動脂質代謝有關酶的基因轉錄，從而促進脂肪氧化分解；其mRNA表達水平越高，越有利于脂肪氧化分解，改善動脈粥樣硬化癥狀[21]。本研究結果顯示，模型組PPAR-γ、HMG-CoA還原酶、FXR mRNA表達水平低于對照組；辛伐他汀組PPAR-γ、HMG-CoA還原酶、ABCA1、LXR-α、FXR mRNA表達水平高于模型組，HMG-CoA還原酶、ABCA1、LXR-α、FXR mRNA表達水平高于對照組；原花青素組PPAR-γ、HMG-CoA還原酶、ABCA1、LXR-α、FXR mRNA表達水平高于對照組、模型組，HMG-CoA還原酶mRNA表達水平高于辛伐他汀組。上述結果證明，原花青素治療PCOS合并動脈粥樣硬化效果顯著，甚至強于臨床常用藥辛伐他汀。

由于本研究樣本量小，臨床代表性差，進一步的治療效果還需要臨床試驗研究；且PCOS合并動脈粥樣硬化的發(fā)病機制需進一步明確，因而本研究未能確定原花青素的具體治療機制，有待進一步的研究探討。

綜上所述，原花青素可改善PCOS合并動脈粥樣硬化模型大鼠脂代謝水平，并縮減動脈粥樣斑塊。

作者貢獻：金鉉順、李夢京、金石、張國杰、元奎昌進行文章的構思與設計、研究的實施與可行性分析、數(shù)據(jù)收集、數(shù)據(jù)整理、統(tǒng)計學處理、結果的分析與解釋、撰寫論文、論文的修訂、英文的修訂，金鉉順負責文章的質量控制及審校、對文章整體負責、監(jiān)督管理。

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(本文編輯：崔麗紅)

Effect of Procyanidine on Rat Models of Polycystic Ovary Syndrome Complicated with Atherosclerosis

JINXuan-shun,LIMeng-jing,JINShi,ZHANGGuo-jie,YUANKui-chang*

DepartmentofCardiology,YanbianUniversityHospital,Yanji133000,China

*Correspondingauthor:YUANKui-chang,Associatechiefphysician;E-mail:7250599@qq.com

Objective To explore the effect and mechanism of procyanidine on rat models of polycystic ovary syndrome(PCOS) complicated with atherosclerosis.Methods This study was conducted between January and October 2015.For modeling the rats of PCOS complicated with atherosclerosis,we randomly assigned 20 female healthy and clean SD rats to control group(n=5,conventional feeding) and modeling group〔n=15,embedding and regular replacement of dihydrotestosterone(DHT) sustained-release tablets in the subcutaneous tissue of the neck and back and giving enough high-fat food,pellet and water〕.Body weight,androgen,leptin and insulin levels were measured in both groups after 16 weeks of intervention.Aortic tunica intima specimen was taken from both groups and detected by optical microscopy,and the results suggested that the rat models of PCOS complicated with arteriosclerosis were successfully built only in modeling group.Then we randomly divided modeling group into model subgroup,simvastatin subgroup and procyanidine subgroup with 5 rats in each.Both control group and model subgroup were fed with 10 ml/kg 0.9% sodium chloride solution,simvastatin subgroup and procyanidine subgroup were fed with 4 mg/kg simvastatin tablets,50 mg/kg procyanidine,respectively,once a day,for 4 weeks.At the end of this round of intervention,the rat tail vein blood was taken for measuring the levels of lipid metabolism indicators 〔total cholesterol(TC),triacylglycerol(TG),low-density lipoprotein(LDL) and high-density lipoprotein(HDL)〕.Then,all the rats were sacrificed,the carotid artery blood was collected to detect the mRNA expressions of lipid metabolism-associated key genes〔peroxisome proliferator-activated receptor gamma(PPAR-γ),3-hydroxy-3-methyl-glutaryl-CoA(HMG-CoA) reductase,ATP-binding cassette transporter A1(ABCA1),liver X receptor alpha(LXR-α) and farnesoid X receptor(FXR)〕.Results Modeling group had lower body weight,androgen,leptin and insulin levels than control group(P<0.05).There were a lot of atherosclerotic plaques and cholesterol crystals in the aortic tunica intima of modeling group but not in control group found by optical microscopy.TC,TG and LDL levels were higher in model subgroup than in control group(P<0.05);simvastatin subgroup had lower TC,TG and LDL levels but higher HDL level than model subgroup(P<0.05);higher HDL level was noted in simvastatin subgroup than in control group(P<0.05);procyanidine subgroup had lower TC,TG,LDL levels but higher HDL level than model subgroup,lower TC and LDL levels than simvastatin subgroup,and higher HDL level than control group(P<0.05).Compared with control group,model subgroup had lower PPAR-γ,HMG-CoA reductase and FXR mRNA expressions(P<0.05);the mRNA expressions of all the 5 genes were higher in simvastatin subgroup than in model subgroup(P<0.05);HMG-CoA reductase,ABCA1,LXR-α and FXR mRNA expressions were higher in simvastatin subgroup than in control group(P<0.05);procyanidine subgroup had higher PPAR-γ,HMG-CoA reductase,ABCA1,LXR-α,FXR mRNA expressions than both control group and model subgroup,and it had higher HMG-CoA reductase mRNA expression than simvastatin subgroup(P<0.05).Optical microscopy displayed that,much more atherosclerotic plaques and cholesterol crystals appeared in the aortic tunica intima in model subgroup than in control group;atherosclerotic plaques and cholesterol crystals were less in simvastatin subgroup than in model subgroup;procyanidine group showed even less atherosclerotic plaques and cholesterol crystals than simvastatin subgroup.Conclusion Procyanidine could be used to improve the lipid metabolism and reduce the atherosclerotic plaques in rats with PCOS complicated with atherosclerosis.

Polycystic ovary syndrome;Atherosclerosis;Proanthocyanidins;Rats;Simvastatin

國家自然科學基金資助項目(81460229)；吉林省教育廳“十二五”科學技術研究項目(吉教科合字[2012]第18號)；延邊大學科技發(fā)展計劃項目〔延大科合字(2011)第13號〕

R 711.75 R 543.5

A

10.3969/j.issn.1007-9572.2017.12.011

2016-11-23；

2017-02-21)

133000 吉林省延吉市，延邊大學附屬醫(yī)院心內科

*通信作者：元奎昌，副主任醫(yī)師；E-mail：7250599@qq.com