張姝萍，王岳飛，徐平

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茶多酚對(duì)動(dòng)脈粥樣硬化的預(yù)防作用與機(jī)理研究進(jìn)展

張姝萍，王岳飛，徐平*

浙江大學(xué)茶學(xué)系，浙江 杭州 310058

動(dòng)脈粥樣硬化是多種心血管疾病的重要病理基礎(chǔ)，對(duì)心腦血管的損害可累及全身各個(gè)器官。茶多酚能夠通過抗炎、調(diào)節(jié)血脂水平、抑制LDL氧化修飾、改善內(nèi)皮功能、保持斑塊穩(wěn)定性等不同途徑有效預(yù)防動(dòng)脈粥樣硬化。本文就近年來(lái)茶多酚對(duì)動(dòng)脈粥樣硬化的預(yù)防功能與機(jī)理方面的研究進(jìn)行綜述。

動(dòng)脈粥樣硬化；茶多酚；心血管；抗炎；平滑肌細(xì)胞增殖

心血管疾?。–ardiovascular disease，CVD）是全球的頭號(hào)死因[1]。2017年世界衛(wèi)生組織報(bào)道，CVD是嚴(yán)重威脅人類健康的重大疾病，死亡人數(shù)約占全球死亡總數(shù)的31%[2]。《中國(guó)心血管病報(bào)告2017》顯示，我國(guó)CVD死亡占居民總死亡原因的首位，高于腫瘤和其他疾病，每5例死亡中就有2例死于CVD[3]。我國(guó)CVD患病率仍在持續(xù)上升，其中以冠狀動(dòng)脈粥樣硬化性心臟病占比最高。

動(dòng)脈粥樣硬化（Atherosclerosis，AS）是心血管疾病的重要病理基礎(chǔ)（圖1）[4-6]。AS形成機(jī)制極其復(fù)雜，一直是心血管疾病研究的熱點(diǎn)。AS為多因素所致，以動(dòng)脈壁內(nèi)脂質(zhì)沉著，形成粥糜狀的病灶以及纖維增生，使管壁硬化為特征[5]。雖然每年關(guān)于AS的論文超過13?000篇，但目前依然未能找到有效的預(yù)防機(jī)制以及確切的診治方法。一般認(rèn)為，AS的發(fā)生機(jī)制涉及到血管內(nèi)皮受損、氧自由基損傷、脂質(zhì)沉著、血小板黏附聚集、炎性細(xì)胞浸潤(rùn)、血管平滑肌細(xì)胞內(nèi)鈣超負(fù)荷、病理性血管新生與局部血栓形成等多項(xiàng)環(huán)節(jié)[7]。目前AS的治療藥物主要為他汀類藥物（調(diào)脂藥物）、替格瑞洛（抗血小板藥物）與CCB（鈣拮抗劑）等。AS的成因復(fù)雜，藥物防治難度大，且大多具有副作用，因此早期預(yù)防和控制非常重要。

圖1 動(dòng)脈粥樣硬化在心血管疾病中的作用[4-6]

茶多酚是茶葉中最重要的活性物質(zhì)之一，具有抗氧化、抗炎、抗菌和抗癌等多種功效。其中茶多酚在預(yù)防動(dòng)脈粥樣硬化，保護(hù)心血管方面的作用一直備受重視，在體外研究和動(dòng)物模型中得到證實(shí)。本文綜述了茶多酚的抗動(dòng)脈粥樣硬化作用及其機(jī)理的研究進(jìn)展。

1 茶多酚對(duì)AS的預(yù)防作用

1.1 流行病學(xué)

由于老齡化與飲食不均衡等因素，AS的患者數(shù)量逐年增加。近年來(lái)關(guān)于茶對(duì)人體心血管疾病改善功能的記錄見表1，結(jié)果均顯示茶葉消費(fèi)量與心血管疾病防治具有相關(guān)性。但不同茶類的作用效果存在差異，針對(duì)不同性別人群的作用效果也存在差異。新近荷蘭一項(xiàng)調(diào)查研究表明，每日飲用2~3杯綠茶可以顯著降低男性的CVD患病風(fēng)險(xiǎn)，但在女性中未觀察到相關(guān)性[21]。2016年日本的一項(xiàng)調(diào)查結(jié)果也顯示，飲用綠茶與以AS為病理基礎(chǔ)的冠心病發(fā)病率降低有關(guān)，且在60歲以上、超重或患有糖尿病的男性中兩者相關(guān)性更高[22]。

1.2 體外試驗(yàn)

大量臨床資料及試驗(yàn)數(shù)據(jù)證明了血漿中的低密度脂蛋白（Low density lipoprotein，LDL）發(fā)生氧化，生成氧化型低密度脂蛋白（Oxidized low density lipoprotein，ox-LDL）是導(dǎo)致AS的主要危險(xiǎn)因素[23]。在AS形成早期，血液中的單核細(xì)胞進(jìn)入內(nèi)皮下間隙，在內(nèi)膜下被激活后分化成為巨噬細(xì)胞，且通過清道夫受體無(wú)反饋性吞噬大量ox-LDL，致使細(xì)胞內(nèi)脂質(zhì)堆積，形成泡沫細(xì)胞。其大致過程如圖2[24]所示。

通常選取U937單核細(xì)胞模型和人血管內(nèi)皮細(xì)胞模型模仿AS早期單核細(xì)胞進(jìn)入內(nèi)皮下間隙的過程。腫瘤壞死因子（Tumor necrosis factor alpha，TNF-）作為一種強(qiáng)效的促炎因子，可通過多種信號(hào)通路介導(dǎo)炎癥反應(yīng)，是AS形成過程中的重要因素[25]。因此TNF-常在體外試驗(yàn)中用于刺激細(xì)胞誘導(dǎo)炎癥。

在U937單核細(xì)胞模型中，EGCG（10?μmol·L-1，30?μmol·L-1）可以抑制由TNF-誘導(dǎo)的炎癥因子表達(dá)上調(diào)，抑制U937單核細(xì)胞黏附于人ISO-HAS內(nèi)皮細(xì)胞，同時(shí)下調(diào)ISO-HAS細(xì)胞凋亡和自噬[23]。Li等[26]發(fā)現(xiàn)EGCG（1~10?μmol·L-1）可以劑量依賴性地下調(diào)U937單核細(xì)胞中由血管緊張素II（Angiotensin II，AngII）和白細(xì)胞介素-6（Interleukin-6，IL-6）誘導(dǎo)產(chǎn)生的C反應(yīng)蛋白（C-reaction protein，CRP），而CRP作為炎性細(xì)胞因子直接參與粥樣斑塊形成。

Wang等[27]發(fā)現(xiàn)，1~10?μmol·L-1的EGCG處理可以降低內(nèi)皮素-1（Endothelin-1，ET-1）誘導(dǎo)的血管平滑肌細(xì)胞CRP積累，阻斷活性氧信號(hào)，減輕AS相關(guān)炎癥反應(yīng)。Won等[28]發(fā)現(xiàn)，綠茶兒茶素（20?μmol·L-1，50?μmol·L-1）可抑制AngII誘導(dǎo)的血管平滑肌細(xì)胞增殖，且該抑制作用與MAPK信號(hào)通路有關(guān)。

1.3 動(dòng)物試驗(yàn)

載脂蛋白（Apolipoprotion E）基因敲除小鼠（ApoE-/-小鼠）可在正常飼料喂養(yǎng)下產(chǎn)生嚴(yán)重的高膽固醇血癥，自發(fā)形成AS斑塊，且斑塊分布和病理特征與人類AS斑塊相似，是研究AS病程及干預(yù)效果的理想動(dòng)物模型[29]。Chyu等[30]每天給ApoE-/-小鼠注射10?mg·kg-1的EGCG溶液（處理時(shí)間分別設(shè)21?d與42?d），結(jié)果發(fā)現(xiàn)，21?d EGCG處理組小鼠頸總動(dòng)脈外膜損傷致內(nèi)膜病變而引起的AS斑塊面積比對(duì)照組小55%，42?d EGCG處理組AS斑塊面積比對(duì)照組小73%。Mika等[31]連續(xù)12周用高脂飼料與綠茶兒茶素（90?mg·kg-1）同時(shí)喂養(yǎng)ApoE-/-小鼠，結(jié)果顯示，在整個(gè)主動(dòng)脈與主動(dòng)脈根部截面上，AS斑塊面積分別減少28%與45%。Hayek等[32]給ApoE-/-小鼠喂食富含兒茶素的水（50?μg·d-1），6周后，兒茶素處理組小鼠主動(dòng)脈AS斑塊面積與對(duì)照組相比小39%，并且兒茶素組小鼠體內(nèi)LDL的氧化敏感性有所降低。Morrison等[33]按照西式飲食方式，在雌性ApoE-/-leiden小鼠的飲食中補(bǔ)充1%的膽固醇，4周之后將小鼠分為兩組，保持高膽固醇飲食并給其中一組喂食兒茶素，另一組則為對(duì)照組。20周后，兒茶素組小鼠每日攝入兒茶素量為(110±11)?mg·kg-1（兒茶素/小鼠體重），且該組小鼠平均AS病變面積相比對(duì)照組減小27%。在雄性ApoE-/-小鼠模型中，連續(xù)6周含0.02%的兒茶素的飲食可使小鼠平均AS病變面積減小32%[34]。

表1 茶葉消費(fèi)與心血管疾病的關(guān)系研究

注：一般來(lái)說(shuō)，沖泡后的綠茶與烏龍茶每杯（237?mL）中EGCG含量為126.5~548.5?μg·mL-1，紅茶中EGCG含量為0~295.3?μg·mL-1 [20]

Note: Generally speaking, the content of EGCG in each cup (237?mL) of brewed green tea and oolong tea is 126.5-548.5?μg·mL-1, and that in black tea is 0-295.3?μg·mL-1[20]

注：（1）血流中的ox-LDL刺激單核細(xì)胞上調(diào)CD11b/CD18粘附分子的表達(dá)，（2）平滑肌細(xì)胞和內(nèi)皮細(xì)胞產(chǎn)生活性氧，LDL進(jìn)入內(nèi)皮之后，在活性氧的作用下被氧化成為ox-LDL。ox-LDL可誘導(dǎo)內(nèi)皮功能障礙，（3）ox-LDL誘導(dǎo)促炎細(xì)胞因子的表達(dá)，如MCP-1，（4）ox-LDL誘導(dǎo)生長(zhǎng)因子和幾種細(xì)胞表面粘附分子的表達(dá)，細(xì)胞表面粘附分子促使單核細(xì)胞和T淋巴細(xì)胞進(jìn)入內(nèi)膜，（5、6）ox-LDL激活單核細(xì)胞向巨噬細(xì)胞的發(fā)育，巨噬細(xì)胞通過清道夫受體無(wú)反饋性吞噬大量ox-LDL，（7）ox-LDL刺激細(xì)胞增殖和平滑肌細(xì)胞遷移，（8）ox-LDL抑制巨噬細(xì)胞的遷移。圖中箭頭表示激活或誘導(dǎo)，豎線表示抑制或阻礙

2 作用機(jī)理

2.1 抗炎作用

2.1.1 下調(diào)AS相關(guān)炎癥因子

大量試驗(yàn)研究與臨床觀察證實(shí)，受損內(nèi)皮細(xì)胞分泌多種炎癥因子以及生長(zhǎng)因子，誘導(dǎo)單核-巨噬細(xì)胞通過免疫球蛋白超家族、整合素家族與內(nèi)皮細(xì)胞進(jìn)行黏附，進(jìn)而進(jìn)入到內(nèi)皮細(xì)胞下，是AS的誘因[26,35-36]。Ross[7]和Libby[4]的炎癥學(xué)說(shuō)認(rèn)為，某些脂類如溶血磷脂、氧化固醇等作為信號(hào)分子，與內(nèi)皮細(xì)胞的受體結(jié)合后可以激活許多促炎細(xì)胞因子的基因表達(dá)，如單核細(xì)胞趨化蛋白-l（Monocyte chemoattractant protein-1，MCP-1）、血管-細(xì)胞粘附分子（Vascular cell adhesion molecular-1，VCAM-1）、細(xì)胞間粘附分子（Intercellular adhesion molecular-1，ICAM-1）、內(nèi)皮細(xì)胞白細(xì)胞粘附分子（E-selectin）等。當(dāng)巨噬細(xì)胞被激活時(shí)，會(huì)分泌致炎因子如白細(xì)胞介素-1（Interleukin-1，IL-1）、IL-6、TNF-與CRP等，這些炎癥因子直接參與粥樣斑塊形成[26]。茶多酚能夠下調(diào)AS相關(guān)炎癥因子的表達(dá)。

VCAM-1和ICAM-1在白細(xì)胞粘附于血管內(nèi)皮細(xì)胞表面并進(jìn)入內(nèi)皮下，以及在平滑肌細(xì)胞增殖中起到重要作用[35]。Chae等[37]通過體外研究發(fā)現(xiàn)，10~50?μmol·L-1EGCG處理可顯著抑制人臍靜脈血管內(nèi)皮細(xì)胞（Human umbilical vein endothelial cells，HUVEC）中由AngII誘導(dǎo)的VCAM-1與ICAM-1相關(guān)mRNA合成，以及減少HUVEC細(xì)胞膜上的VCAM-1和ICAM-1分子。Ludwig等[38]發(fā)現(xiàn)，EGCG（10~100?μmol·L-1）可劑量依賴性地抑制由IL-1誘導(dǎo)的HUVEC細(xì)胞內(nèi)VCAM-1表達(dá)，并抑制TNF-誘導(dǎo)的THP-1單核細(xì)胞粘附于血管內(nèi)皮細(xì)胞。

MCP-1是一種對(duì)于單核細(xì)胞、嗜堿性粒細(xì)胞、記憶性T細(xì)胞有效的化學(xué)吸引蛋白質(zhì)[39]，血清中MCP-1含量升高是冠狀動(dòng)脈疾病風(fēng)險(xiǎn)的炎癥標(biāo)志物之一[36]。早期研究顯示，在人類[40]和靈長(zhǎng)類動(dòng)物[41]中，可以觀察到AS斑塊中MCP-1相關(guān)mRNA的表達(dá)有所增加，表明了MCP-1在動(dòng)脈壁中介導(dǎo)單核細(xì)胞浸潤(rùn)的潛在作用。Wang等[42]研究表明，EGCG（10、25、50?μmol·L-1）在HUVEC細(xì)胞中抑制TNF-誘導(dǎo)的MCP-1產(chǎn)生，且抑制效果呈現(xiàn)劑量依賴關(guān)系。Ahn等[39]發(fā)現(xiàn)，EGCG（10、30、50?μmol·L-1）可劑量依賴性地抑制牛冠狀動(dòng)脈微血管內(nèi)皮細(xì)胞內(nèi)Akt的磷酸化以及TNF-受體1（TNF-receptor 1，TNFR1）上的TNF因子活化，從而減少M(fèi)CP-1的產(chǎn)生。

CRP作為炎性細(xì)胞因子直接參與粥樣斑塊形成。Ramesh等[43]用高脂飲食建立AS大鼠模型，研究EGCG的抗AS作用。結(jié)果表明，給AS大鼠腹腔注射EGCG（100?mg·kg-1）兩周，可顯著降低CRP的表達(dá)，降低炎癥血液學(xué)參數(shù)（紅細(xì)胞沉降率、白細(xì)胞總數(shù)等），說(shuō)明EGCG的抗AS功效與抗炎作用密切相關(guān)。

2.1.2 調(diào)節(jié)信號(hào)轉(zhuǎn)導(dǎo)通路

茶多酚可以影響細(xì)胞內(nèi)多條與AS相關(guān)的炎性信號(hào)通路，目前研究表明它主要可以作用于核因子活化B細(xì)胞κ輕鏈增強(qiáng)子（Nuclear factor kappa-light-chain-enhancer of activated B cells，NF-κB）信號(hào)通路、絲裂原活化蛋白激酶（Mitogen-activated protein kinase，MAPK）/NF-κB信號(hào)通路、NF-κB/Notch信號(hào)通路、微小RNA（MicroRNA，miRNA）信號(hào)通路等。

大量研究證實(shí)，NF-κB信號(hào)通路是調(diào)控轉(zhuǎn)錄多種炎性因子的中心環(huán)節(jié)和共同通路，與AS的發(fā)生發(fā)展密切相關(guān)[37,44]。茶多酚不是NF-κB信號(hào)通路的特異性抑制劑，但能部分抑制NF-κB信號(hào)通路，顯著下調(diào)炎癥因子包括黏附分子、細(xì)胞因子和基質(zhì)金屬蛋白酶的表達(dá)，發(fā)揮抗AS的作用[23]。Wang等[42]發(fā)現(xiàn)，EGCG在HUVEC細(xì)胞中阻斷67?kDa層粘連蛋白受體介導(dǎo)的NF-κB信號(hào)通路，從而抑制HUVEC細(xì)胞產(chǎn)生炎癥因子MCP-1。除了EGCG對(duì)NF-κB信號(hào)通路活化有良好的抑制作用之外[42,45]，ECG也能顯著抑制由TNF-α誘導(dǎo)的NF-κB通路活化，抑制促炎因子的分泌，抑制炎癥進(jìn)程[46]。

MAPK信號(hào)通路在調(diào)節(jié)細(xì)胞增殖、分化、轉(zhuǎn)化以及凋亡方面起到重要作用[47-49]。MAPK通路中的3種激酶在內(nèi)皮的損傷和保護(hù)中起關(guān)鍵作用[47,49]，包括細(xì)胞外信號(hào)調(diào)節(jié)激酶（Extracellular signal-regulated kinases，ERK），c-Jun氨基末端激酶（c-Jun-N-terminal kinase，JNK）和p38蛋白激酶（p38 MAPK）。ERK一般被有絲分裂原和生長(zhǎng)因子激活，介導(dǎo)細(xì)胞增殖；p38 MAPK和 JNK激酶的激活則源于應(yīng)激反應(yīng)，介導(dǎo)細(xì)胞應(yīng)激和凋亡[47,49]，其中p38 MAPK與NF-κB之間形成的相互激活網(wǎng)絡(luò)能調(diào)控多種炎癥介質(zhì)的基因表達(dá)，促進(jìn)AS的發(fā)生發(fā)展。Yang等[50]發(fā)現(xiàn)，在Ang II誘導(dǎo)的HUVEC細(xì)胞模型中，EGCG（5~25?μmol·L-1）可以抑制Ang II誘導(dǎo)的p38 MAPK和JNK1/2激酶活化，減小Ang II引起的內(nèi)皮功能障礙。Chae等[37]發(fā)現(xiàn)EGCG（10~50?μmol·L-1）對(duì)抗HUVEC炎癥和黏附反應(yīng)是通過抑制p38 MAPK信號(hào)通路實(shí)現(xiàn)的，EGCG抑制了MAPK通路中p38 MAPK和ERK的磷酸化。

許多研究表明Notch信號(hào)通路在AS的炎癥反應(yīng)中起到重要作用[51-53]。研究顯示，在受損的心肌和血管中，Notch的配體和受體數(shù)量都有所增加[54-56]。Xie等[57]用尿酸刺激建立HUVEC體外炎癥模型，發(fā)現(xiàn)用EGCG（20?μmol·L-1）進(jìn)行預(yù)處理能有效抑制細(xì)胞中Notch信號(hào)通路，并顯著抑制炎癥因子MCP-1、IL-6和TNF-的分泌，減少炎癥因子對(duì)內(nèi)皮細(xì)胞的損傷。

miRNA是一類廣泛存在于動(dòng)植物體內(nèi)的非編碼單鏈小分子RNA，通過與特異性靶信使結(jié)合，在轉(zhuǎn)錄后水平抑制基因表達(dá)。miRNA廣泛參與細(xì)胞分化、生長(zhǎng)發(fā)育、增殖與凋亡等各種過程[58-59]。研究發(fā)現(xiàn)，多種miRNA與AS的進(jìn)程高度相關(guān)[60-61]。而低劑量的茶多酚（10?μmol·L-1）處理48?h即能顯著影響miRNA信號(hào)通路，調(diào)控多種炎癥相關(guān)miRNA的表達(dá)[62]。楊紅霞等[63]發(fā)現(xiàn)，EGCG（25?μmol·L-1，50?μmol·L-1）通過抑制THP-1巨噬細(xì)胞源性泡沫細(xì)胞中的miR-33a信號(hào)通路，進(jìn)而調(diào)控ABCA1（介導(dǎo)細(xì)胞膽固醇流出的主要膜轉(zhuǎn)運(yùn)體）表達(dá)，促進(jìn)巨噬細(xì)胞內(nèi)膽固醇流出。

2.2 調(diào)節(jié)脂質(zhì)代謝異常

2.2.1 調(diào)節(jié)血脂水平

血脂異常是AS重要誘導(dǎo)因素，調(diào)脂治療可預(yù)防AS[4,64]。血漿內(nèi)高水平的低密度脂蛋白膽固醇（Low-density lipoprotein cholesterol，LDL-C）是AS的重要誘因[65]。在動(dòng)物試驗(yàn)[66-68]與人體試驗(yàn)[69-72]中茶多酚的調(diào)節(jié)血脂作用均有報(bào)道。Ikeda等[73]發(fā)現(xiàn)不同單體組合的兒茶素對(duì)大鼠腸道吸收膽固醇有抑制作用，其中以ECG和EGCG的組合效果最佳。Nagao等[16]將270名志愿者分成兩組，其中一組每天飲用340?mL富含綠茶兒茶素（1?714?μg·mL-1）的飲品，另一組每天飲用相同體積的對(duì)照飲品（含綠茶兒茶素283?μg·mL-1），連續(xù)12周后發(fā)現(xiàn)，綠茶兒茶素可以有效降低血壓和血脂，同時(shí)降低血液內(nèi)LDL含量。Imbe等[74]讓志愿者連續(xù)12?d每日飲用600?mL綠茶提取物溶液（含兒茶素1?012.5?μg·mL-1），結(jié)果顯示，受試者總膽固醇和LDL-C水平均顯著降低。

茶多酚還可以加速膽固醇的代謝及促進(jìn)膽固醇的排泄。連續(xù)6周給小鼠喂飼EGCG（0.2%體重、1%體重）可顯著抑制膽固醇合成相關(guān)基因的表達(dá)，上調(diào)肝細(xì)胞中控制將膽固醇轉(zhuǎn)變?yōu)槟懼岬腃YP7A1基因的mRNA表達(dá)，加速小鼠體內(nèi)膽固醇代謝[75]。Hsu等[76]發(fā)現(xiàn)，當(dāng)人攝入高脂飲食時(shí)，飲用富含茶多酚（276.7?μg·mL-1）的烏龍茶可以增加脂類物質(zhì)的排泄量。Muramatsu等[77]用高膽固醇食物喂養(yǎng)大鼠建立高血脂模型，然后將綠茶兒茶素（含EGCG，EGC，ECG和EC）添加進(jìn)入大鼠食物（10~20?g·kg-1），發(fā)現(xiàn)綠茶兒茶素可以顯著增加大鼠糞便中總脂肪與總膽固醇含量。

胰膽固醇脂酶（Pancreatic cholesterol esterase，PCE）是小腸內(nèi)膽固醇吸收的關(guān)鍵酶，胰脂肪酶（Pancreatic lipase，PL）是腸道內(nèi)脂肪吸收的關(guān)鍵酶[78]。PCE與PL作為脂質(zhì)代謝的重要酶，在AS發(fā)生發(fā)展過程中起著重要作用。Jeon等[79]發(fā)現(xiàn)，兒茶素聚合物（125?μmol·L-1）可以顯著抑制PCE和PL的活性。Nakai等[80]從茶葉中分離出54種多酚類物質(zhì)，并檢測(cè)這些多酚物質(zhì)對(duì)PL的抑制作用，發(fā)現(xiàn)其中EGCG的抑制作用最佳。

2.2.2 抑制LDL的氧化修飾

低密度脂蛋白（Low-density lipoprotein，LDL）是血漿中主要的攜帶膽固醇的脂蛋白，它由25%的載脂蛋白B-100（Apolipoprotein- B100，apoB100）和約75%的脂質(zhì)組成[81]。根據(jù)AS的氧化應(yīng)激理論，活性氧（Reactive oxygen species，ROS）導(dǎo)致LDL氧化，生成ox-LDL[82]。氧化產(chǎn)物ox-LDL被單核-巨噬細(xì)胞吞噬，載脂的巨噬細(xì)胞轉(zhuǎn)化為泡沫細(xì)胞并累積，進(jìn)一步導(dǎo)致動(dòng)脈粥樣硬化[83-84]。

LDL氧化涉及脂質(zhì)過氧化與載脂蛋白改性兩個(gè)方面[85]，防止LDL氧化是防治AS的有效方法[84]。越來(lái)越多的科學(xué)研究表明，以茶多酚為代表的膳食多酚有助于抑制LDL氧化，預(yù)防冠心病[86-90]。

茶多酚可以抑制LDL上的apoB100改性[91]。Goto等[92]發(fā)現(xiàn)，EGCG（25?μmol·L-1）通過上調(diào)LDL受體水平和降低apoB100水平改善膽固醇代謝。劉波靜[93]分別用茶多酚（200?mg·kg-l·d-l）和吉非羅齊（200?mg·kg-l·d-l，高血脂癥常用藥物）與高脂飼料一同喂養(yǎng)小鼠，發(fā)現(xiàn)茶多酚和吉非羅齊都具有升高血清apoA1，降低apoBl00和apoBl00/apoAl比值的效果，二者相比茶多酚的作用更為明顯。

茶多酚可以通過清除自由基抑制脂質(zhì)過氧化[91]。自由基可以通過Fen-ton反應(yīng)和Haber-weiss反應(yīng)介導(dǎo)ROS的生成，而ROS與AS發(fā)病進(jìn)程密不可分。ROS與生物膜的磷脂、酶和膜受體相關(guān)的多不飽和脂肪酸的側(cè)鏈及核酸等大分子物質(zhì)起脂質(zhì)過氧化反應(yīng)，形成脂質(zhì)過氧化產(chǎn)物（Lipid Peroxide，LPO）。此外，ROS在ox-LDL介導(dǎo)的內(nèi)皮細(xì)胞毒性中起重要作用，特別是通過激活caspase級(jí)聯(lián)和細(xì)胞凋亡引起內(nèi)皮細(xì)胞損傷[94-96]。茶多酚結(jié)構(gòu)組成中的芳香環(huán)能和羥基結(jié)合，中和自由基，抑制LDL的氧化修飾，從而預(yù)防AS[97-98]。Choi等[99]發(fā)現(xiàn)，EGCG（25?μmol·L-1）可以抑制ox-LDL誘導(dǎo)的ROS產(chǎn)生，從而保護(hù)人血管內(nèi)皮細(xì)胞。Li等[100]研究表明，EGCG（10~100?μmol·L-1）降低AngII誘導(dǎo)的NADPH氧化酶表達(dá)，減少ROS的產(chǎn)生，同時(shí)抑制AngII誘導(dǎo)的NF-κB和蛋白因子-1（Activator protein-1，AP-1）的激活。

過渡元素中金屬元素如鐵、銅等是許多自由基產(chǎn)生過程的催化劑[101]。茶多酚具有鄰苯二酚結(jié)構(gòu)，有較強(qiáng)的絡(luò)合金屬離子的性能[102]。Cu2+促進(jìn)脂質(zhì)過氧化，催化脂質(zhì)過氧化物的分解，生成脂烷氧基和過氧自由基[103]。Fe2+同樣介導(dǎo)脂質(zhì)過氧化，也是·OH等自由基產(chǎn)生的媒介物。Potapovich等[104]的研究表明，茶多酚可螯合巨噬細(xì)胞中的Cu2+、Fe2+等過渡金屬離子，使之失活，從而影響LDL氧化。

細(xì)胞內(nèi)存在自身抗氧化防御系統(tǒng)，能及時(shí)清除體內(nèi)過剩的自由基，維持其動(dòng)態(tài)平衡。這些抗氧化防御系統(tǒng)主要包括抗氧化酶（超氧化物歧化酶SOD、過氧化氫酶CAT、谷胱甘肽過氧化物酶GSH-Px、谷胱甘肽硫轉(zhuǎn)移酶 GSTs等）和一些低分子化合物（VE、VC以及谷胱甘肽等），它們可以增強(qiáng)機(jī)體抗氧化防御能力，抑制脂質(zhì)過氧化水平。而茶多酚作為中間抗氧化劑，可與以上物質(zhì)進(jìn)行協(xié)同抗氧化，從而更好地發(fā)揮防御系統(tǒng)的功能，保持體內(nèi)自由基的動(dòng)態(tài)平衡。趙秀蘭等[105]用高脂飼料喂養(yǎng)試驗(yàn)家兔建立AS模型，并用含茶多酚（0.2%、0.4%）的飲用水與高脂飼料一同進(jìn)行喂養(yǎng)。結(jié)果顯示，茶多酚組的家兔體內(nèi)SOD與GSH-Px活力升高，血清中脂質(zhì)過氧化產(chǎn)物MDA的含量降低，AS發(fā)展受到抑制，表明茶多酚可以穩(wěn)固機(jī)體的氧化還原平衡并抑制LDL的氧化。Jayashree等[106]發(fā)現(xiàn)，連續(xù)一周給小鼠喂食綠茶提取物（50?mg·kg-1，100?mg·kg-1，200?mg·kg-1）可以抑制由喂食Patulin（2?mg·kg-1）導(dǎo)致的SOD、CAT、GSH-Px活力減弱，從而減小氧化損傷。此外，茶多酚也可以促進(jìn)VC、VE等胞內(nèi)低分子抗氧化劑修復(fù)再生和循環(huán)利用，從而抑制LDL氧化[107-108]。

2.3 改善內(nèi)皮功能

2.3.1 抑制內(nèi)皮細(xì)胞凋亡

血管內(nèi)皮細(xì)胞（Endothelial cells，ECs）凋亡是AS病理發(fā)生的早期事件，可促進(jìn)粥樣硬化病變形成、斑塊侵蝕和急性冠脈綜合征（Acute Coronary Syndromes，ACS）發(fā)展[109]。ECs損傷和AS前期形成的多種危險(xiǎn)因素可誘導(dǎo)ECs凋亡。茶多酚可通過抑制ECs凋亡延緩AS病變進(jìn)程，這種對(duì)ECs凋亡的抑制作用與其抑制caspase家族的激活與超常表達(dá)相關(guān)。

Caspase家族是細(xì)胞凋亡過程中的關(guān)鍵元件，其激活與超常表達(dá)均會(huì)引起細(xì)胞凋亡。茶多酚作為一種caspase抑制劑可以有效抑制ox-LDL介導(dǎo)的ECs凋亡[110-111]。Jeong等[112]發(fā)現(xiàn)，茶多酚抑制ox-LDL介導(dǎo)的血管內(nèi)皮細(xì)胞凋亡是通過阻礙內(nèi)皮細(xì)胞凋亡信號(hào)級(jí)聯(lián)實(shí)現(xiàn)的。

細(xì)胞凋亡相關(guān)基因bcl-2家族通常可以抑制細(xì)胞凋亡，但是其組分bax基因卻起促進(jìn)凋亡的作用[113]。ox-LDL使促進(jìn)凋亡的bax基因過度表達(dá)，且減少bcl-2和bcl-XL的表達(dá)[111]。在H2O2誘導(dǎo)凋亡的鼠平滑肌細(xì)胞模型中， 10~150?μmol·L-1的EGCG預(yù)處理可顯著增加bcl-2基因的表達(dá)水平，降低bax基因的表達(dá)，同時(shí)降低由H2O2刺激引起的caspase-3，caspase-8與caspase-9水平升高[114]。

2.3.2 調(diào)控NO產(chǎn)生，改善內(nèi)皮依賴性舒血管作用

內(nèi)皮型一氧化氮合酶（Endothelial NO synthase，eNOS）減少是動(dòng)脈粥樣硬化過程中主要的代謝紊亂現(xiàn)象之一[115]，它對(duì)血管通透性與血管功能起著重要作用。蛋白激酶Akt和磷酸肌醇3激酶PI3K可以使其激活[116]。一氧化氮（Nitric oxide，NO）是一類內(nèi)皮衍生因子，對(duì)血管通透性和炎癥狀態(tài)非常重要，在內(nèi)皮中受一氧化氮合酶（Endothelial NOS，eNOS）調(diào)節(jié)[117]。NO與AS病程中的許多關(guān)鍵因素有關(guān)，例如LDL氧化、內(nèi)皮白細(xì)胞粘附以及血管平滑肌細(xì)胞增殖等。研究表明，在具有AS癥狀的內(nèi)皮細(xì)胞中，eNOS相關(guān)mRNA水平出現(xiàn)下調(diào)。Xuan等[68]發(fā)現(xiàn)，EGCG（10?mg·L-1）通過激活PI3K/Akt信號(hào)通路，上調(diào)血管內(nèi)皮細(xì)胞NO水平，降低細(xì)胞內(nèi)caspase-3水平，保護(hù)內(nèi)皮細(xì)胞。還有研究表明，EGCG通過PI3K/Akt信號(hào)通路增加血管內(nèi)皮細(xì)胞內(nèi)eNOS的產(chǎn)生量，使細(xì)胞內(nèi)NO量增加，并提高胰島素敏感性，從而改善內(nèi)皮功能[96,118]。Liu等[119]發(fā)現(xiàn)，Hcy可以抑制HUVEC細(xì)胞產(chǎn)生eNOS，而EGCG（3~30?μmol·L-1）可以顯著改善這一現(xiàn)象，同時(shí)EGCG抑制細(xì)胞內(nèi)的促凋亡因子caspase-3和caspase-9的表達(dá)。EGCG保護(hù)內(nèi)皮功能的示意圖見圖3。

2.4 保持斑塊穩(wěn)定性

2.4.1 調(diào)節(jié)關(guān)鍵酶活性

穩(wěn)定性差的AS斑塊易發(fā)生破裂，導(dǎo)致急性心血管事件，這是冠心病的主要死因[120]。脂質(zhì)核心的成分及纖維帽的厚度是決定AS斑塊是否穩(wěn)定的關(guān)鍵因素。AS斑塊中的細(xì)胞外基質(zhì)過度降解會(huì)使斑塊的膠原含量減少，纖維帽變薄，從而導(dǎo)致斑塊不穩(wěn)定。基質(zhì)金屬蛋白酶（Matrix metalloproteinase，MMP）是一類具有降解細(xì)胞外基質(zhì)活性的蛋白酶超家族，其中的成員MMP-9與AS斑塊的不穩(wěn)定性尤其相關(guān)[121-122]。MMPs組織抑制因子（Tissue inhibitor of metalloproteinase，TIMP）是內(nèi)源性的MMP-9拮抗劑，能夠抑制MMP-9的活化，減弱其降解細(xì)胞外基質(zhì)的能力。

茶多酚能抑制MMPs的表達(dá)，增加TIMP的表達(dá)，從而抑制細(xì)胞外基質(zhì)過度降解，維持斑塊穩(wěn)定。在體外試驗(yàn)中，EGCG（1~10?μmol·L-1）可以抑制人主動(dòng)脈血管平滑肌細(xì)胞中MMP-2的活化，并上調(diào)MMP-2的組織抑制劑TIMP-2蛋白的表達(dá)[123]。Bolduc等[124]使用含兒茶素（30?mg·kg-1·d-1）的飲用水喂養(yǎng)自發(fā)性動(dòng)脈粥樣硬化（ATX）LDLr-/-:hApoB+/+小鼠3個(gè)月，發(fā)現(xiàn)兒茶素可以抑制ATX小鼠體內(nèi)由ROS誘導(dǎo)的MMP-9活化以及血管平滑肌細(xì)胞增殖。Cheng等[125]用含綠茶提取物（1?mg·mL-1）的飲用水（42.3±9.4?mL·d-1）喂養(yǎng)雄性Wister大鼠，一周后損傷大鼠左頸總動(dòng)脈，然后繼續(xù)用相同的飲用水喂養(yǎng)大鼠兩周，結(jié)果發(fā)現(xiàn)綠茶提取物組的大鼠左頸總動(dòng)脈內(nèi)膜增生顯著減少，左頸總動(dòng)脈內(nèi)膜面積比對(duì)照組小30%，且綠茶提取物抑制了大鼠受損動(dòng)脈中MMP-2的活化，上調(diào)了TIMP-2的表達(dá)。

2.4.2抗血小板活性

茶多酚具有抗血小板與抗血栓形成的作用[126-127]。通過抗血小板治療可以減少局部血栓形成、抑制血管炎癥，從而穩(wěn)定易損的AS斑塊。正常血小板具有四種功能，即活化、黏附、聚集和分泌。在一些刺激因素（如凝血酶、腎上腺素、血栓素A2）的作用下，血小板糖蛋白GPⅡb/Ⅲa與纖維蛋白原結(jié)合，促血小板聚集，導(dǎo)致血栓形成以及纖維蛋白的沉積?；罨蟮难“蹇舍尫派L(zhǎng)因子，誘導(dǎo)血管平滑肌細(xì)胞遷移與增殖。所以抑制血小板活化在AS防治中非常重要。

注：LOX-1為低密度脂蛋白受體-1；圖中箭頭表示激活或誘導(dǎo)，豎線表示抑制或阻礙

茶多酚具有抗血栓與抗凝血作用。研究發(fā)現(xiàn)，茶多酚可以抑制膠原、ADP、腎上腺素與鈣離子載體等不同刺激因素誘導(dǎo)的離體血小板聚集[128-130]。體內(nèi)研究表明，灌胃或通過飲食攝入茶多酚可不同程度地抑制血小板聚集及血小板活性因子的合成活性[128,131-132]。Chen等[131]以0.5、1?g·kg-1·d-1EGC灌胃小鼠30?d，發(fā)現(xiàn)EGC顯著抑制小鼠的血小板聚集，抑制率分別達(dá)18.4%和25.6%，高劑量組小鼠中內(nèi)源性的活化凝血激酶時(shí)間也顯著延長(zhǎng)。Choi等[132]發(fā)現(xiàn)，攝入兒茶素可顯著抑制慢性鎘中毒大鼠的血小板血栓素A2增加，從而達(dá)到抑制血小板聚集，調(diào)節(jié)炎癥的作用。試驗(yàn)表明，在人體內(nèi)茶多酚也存在抗血小板活化的作用。在一項(xiàng)針對(duì)75名健康男性的試驗(yàn)中，受試者每日服用250?mL紅茶提取物溶液（兒茶素含量為268.8?μg·mL-1），6周后其血液中單核細(xì)胞-血小板聚集體以及嗜中性粒細(xì)胞-血小板聚集體均有減少，說(shuō)明長(zhǎng)期飲茶或可減弱血小板活化反應(yīng)[133]。

然而，也有研究指出，飲茶對(duì)冠狀動(dòng)脈疾病患者的血小板聚集活性無(wú)顯著作用。Duffy等[134]將49名冠狀動(dòng)脈疾病的患者隨機(jī)分成兩組，一組每日服用900?mL紅茶（兒茶素含量約130?μg·mL-1），另一組則飲用同量的水。8周后，2組患者的體外血小板聚集活性無(wú)明顯差異。但因本試驗(yàn)中的患者同時(shí)在服用阿司匹林，故在不服用阿司匹林藥物的情況下，紅茶對(duì)血小板聚集活性的影響仍未明晰。

2.4.3 對(duì)抗病理性血管生成

目前多數(shù)學(xué)者認(rèn)為，血管生成分為生理性和病理性血管生成兩部分[135]。病理性血管新生是很多炎性疾病的特征，這些新生血管可以誘發(fā)AS斑塊的破裂?？寡苌莎煼梢苑€(wěn)定易損AS斑塊，抑制血管進(jìn)一步變窄和炎癥發(fā)展[136]。

血管平滑肌細(xì)胞（Vascular smooth muscle cells，VSMCs）是AS斑塊主要的細(xì)胞成分，VSMCs的病理性增生是AS發(fā)展過程中的重要步驟。眾多研究表明，一些生長(zhǎng)因子，比如PDGF，VEGF與Ang II等均可以促進(jìn)VSMCs的生長(zhǎng)，在AS的病程中發(fā)揮重要作用[6,136]。在正常血管和早期出現(xiàn)粥樣斑塊的血管中，誘導(dǎo)平滑肌細(xì)胞凋亡可以抑制血管損傷后的病理性內(nèi)膜增生[135]。Ahn等[137]使用EGCG（1~100?μmol·L-1）對(duì)大鼠主動(dòng)脈平滑肌細(xì)胞進(jìn)行預(yù)處理，隨后用PDGF-BB和FCS誘導(dǎo)細(xì)胞病理性生長(zhǎng)，結(jié)果發(fā)現(xiàn)，與對(duì)照組相比，EGCG預(yù)處理可以顯著抑制細(xì)胞中血管內(nèi)皮生長(zhǎng)因子如ERK1/2、VEGF-R1和VEGF-R2的磷酸化，從而抑制平滑肌細(xì)胞的病理性增生。Lin等[138]發(fā)現(xiàn)，EGCG（50?mg·kg-1）可以顯著抑制由Ang II誘導(dǎo)的平滑肌細(xì)胞的遷移與增殖。EGCG抑制VSMCs病理性增殖與遷移的功效的原理，可能是調(diào)節(jié)NF-κB信號(hào)通路，影響胞內(nèi)p53活化[139]，以及降低血小板衍生生長(zhǎng)因子受體b（PDGF-Rb）及其下游信號(hào)靶點(diǎn)ERK1/2的活性[137]。Kavantzas等[140]用高脂喂養(yǎng)A、B兩組雄性新西蘭白兔，同時(shí)在B組的飲食中添加2.5%（︰）的綠茶，17周后發(fā)現(xiàn)，B組白兔VEGF陽(yáng)性染色泡沫細(xì)胞和平滑肌細(xì)胞數(shù)量顯著小于A組，且B組的斑塊面積相比A組（對(duì)照組）減小大約30%。

3 總結(jié)與展望

茶多酚能夠作用于AS形成和進(jìn)展過程的各個(gè)環(huán)節(jié)，降低動(dòng)脈粥樣硬化危險(xiǎn)，主要作用包括：下調(diào)AS相關(guān)炎癥因子，調(diào)節(jié)細(xì)胞信號(hào)通路，調(diào)節(jié)脂質(zhì)代謝異常，改善內(nèi)皮功能，調(diào)節(jié)斑塊穩(wěn)定相關(guān)酶活性，抗血小板活性，對(duì)抗病理性血管生成等。

目前，針對(duì)動(dòng)脈粥樣硬化，以茶多酚為活性成分或食品功能因子研發(fā)的產(chǎn)品較少?？蓪⒉瓒喾幼鳛槎喾N預(yù)防心血管疾病的保健食品的基料，用于開發(fā)具有預(yù)防保健活性的食品、飲料等，發(fā)揮茶多酚對(duì)AS的預(yù)防功效。

茶多酚作為一種天然產(chǎn)物，安全性強(qiáng)，毒副作用弱，且水溶性較好，將茶多酚用作AS輔助藥物的研究具有科學(xué)意義和應(yīng)用價(jià)值。但是，在將茶多酚應(yīng)用到AS臨床研究的過程中，依然存在一些需要解決的問題。其一是茶多酚對(duì)于AS的改善功能在不同年齡、不同性別的人群是否都有效仍存在爭(zhēng)議，其二是人體吸收代謝的復(fù)雜性使到達(dá)血管的茶多酚含量及活性都受到了很大的影響。

就流行病學(xué)中的研究出現(xiàn)的結(jié)論不統(tǒng)一，可能是研究對(duì)象的日常生活方式不同而導(dǎo)致的，比如是否吸煙、日常飲食習(xí)慣是否良好等。關(guān)于流行病學(xué)調(diào)查由于混雜因素而出現(xiàn)的不一致結(jié)果，可以進(jìn)一步加強(qiáng)臨床試驗(yàn)以作補(bǔ)充。

此外，由于試驗(yàn)設(shè)計(jì)不同，體外研究與體內(nèi)環(huán)境之間的差異，以及動(dòng)物試驗(yàn)與在人體內(nèi)功效的差異，使得體外研究、動(dòng)物試驗(yàn)與人體試驗(yàn)研究結(jié)論不完全一致。人體試驗(yàn)時(shí)一般采用口服的方法，生物利用度是影響茶多酚抗AS作用的重要因素。因此可以考慮采用茶多酚改性的方法來(lái)增強(qiáng)茶多酚的吸收與在人體中的活性，助其更好地發(fā)揮作用。此外需要注意的是，人體吸收代謝是一個(gè)復(fù)雜的過程，短期攝入茶多酚與長(zhǎng)期攝入茶多酚產(chǎn)生的預(yù)防AS功效有所不同，當(dāng)長(zhǎng)期攝入茶多酚時(shí)，其在人體內(nèi)的代謝與積累情況還有待進(jìn)一步深入研究。

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Prevention of Tea Polyphenols on Atherosclerosis and Relative Mechanisms

ZHANG Shuping, WANG Yuefei, XU Ping*

Department of Tea Science, Zhejiang University, Hangzhou 310058, China

Atherosclerosis is the pathological basis of many cardiovascular diseases. Its injury to the cardiovascular could cause damage to other organs. Numerous data had indicated that tea polyphenols have a good preventive effect on atherosclerosis, such as anti-inflammatory, regulating blood lipid levels, inhibiting LDL oxidation, improving endothelial function and maintaining the stability of atherosclerotic plaque. The aim of this article is to review the health benefits of tea polyphenols against atherosclerosis and to outline the molecular mechanisms of tea polyphenols in atherosclerosis prevention.

atherosclerosis, tea polyphenols, cardiovascular, anti-inflammatory, vascular smooth muscle cell proliferation

S571.1

A

1000-369X(2019)03-231-16

2018-07-04

2018-09-07

國(guó)家廣東省產(chǎn)學(xué)研合作項(xiàng)目（2016B090918118）

張姝萍，女，碩士研究生，主要從事天然產(chǎn)物與人體健康及其機(jī)理研究。*通信作者：zdxp@zju.edu.cn