載脂蛋白A-I模擬肽的研究進(jìn)展

劉湘，歐志君，李艷，區(qū)景松,5Δ

(1.中山大學(xué)附屬第一醫(yī)院 心臟外科，廣東 廣州 510080；2.中山大學(xué)中山醫(yī)學(xué)院衛(wèi)生部輔助循環(huán)重點(diǎn)實(shí)驗(yàn)室，廣東 廣州 510275；3.中山大學(xué)附屬第一醫(yī)院高血壓血管病科，廣東 廣州 510080；4.中山大學(xué)附屬第一醫(yī)院血管疾病診治國家地方聯(lián)合工程實(shí)驗(yàn)室，廣東 廣州 510080；5.廣東省腦功能與腦疾病重點(diǎn)實(shí)驗(yàn)室，廣東 廣州 510080)

載脂蛋白A-I模擬肽的研究進(jìn)展

劉湘1,2,4，歐志君3,4，李艷1,2,4，區(qū)景松1,2,4,5Δ

(1.中山大學(xué)附屬第一醫(yī)院 心臟外科，廣東 廣州 510080；2.中山大學(xué)中山醫(yī)學(xué)院衛(wèi)生部輔助循環(huán)重點(diǎn)實(shí)驗(yàn)室，廣東 廣州 510275；3.中山大學(xué)附屬第一醫(yī)院高血壓血管病科，廣東 廣州 510080；4.中山大學(xué)附屬第一醫(yī)院血管疾病診治國家地方聯(lián)合工程實(shí)驗(yàn)室，廣東 廣州 510080；5.廣東省腦功能與腦疾病重點(diǎn)實(shí)驗(yàn)室，廣東 廣州 510080)

高密度脂蛋白膽固醇(high density lipoprotein cholesterol，HDL-C)由于其心血管保護(hù)作用而受到廣泛的關(guān)注。研究發(fā)現(xiàn)，正常HDL在機(jī)體內(nèi)起著逆轉(zhuǎn)運(yùn)膽固醇、抗炎、抗氧化和促進(jìn)血管新生等保護(hù)心血管的功能。作為HDL含量最高的蛋白質(zhì)，載脂蛋白A-I(apolipoptrotein A-I，apoA-I)在HDL的各種功能活動(dòng)中起關(guān)鍵作用。根據(jù)apoA-I的兩親性α-螺旋結(jié)構(gòu)特點(diǎn)，設(shè)計(jì)了一系列旨在模擬apoA-I功能的模擬肽。ApoA-I模擬肽的功能和代謝取決于它的氨基酸組成和序列，并被證實(shí)在心血管疾病、感染、炎癥和氧化損傷、代謝綜合征和腫瘤等疾病狀態(tài)下發(fā)揮保護(hù)作用。部分臨床試驗(yàn)肯定了apoA-I模擬肽的效益，但由于其高昂的成本而限制了它的實(shí)際應(yīng)用。

載脂蛋白A-I；心血管疾病；炎癥；代謝綜合征

流行病學(xué)調(diào)查發(fā)現(xiàn)，血漿高密度脂蛋白膽固醇(high density lipoprotein cholesterol，HDL-C)的水平與心血管的患病率呈負(fù)相關(guān)[1]。正常HDL在正常機(jī)體內(nèi)不僅起著逆轉(zhuǎn)運(yùn)膽固醇的作用，同時(shí)還具有抗炎、抗氧化、激活內(nèi)皮一氧化氮合酶(endothelial nitric oxide synthase，eNOS)和促進(jìn)血管新生等功能[2-5]。然而，也有研究顯示HDL-C水平正常的人同樣會(huì)患冠心病，HDL-C水平明顯高于正常人但同時(shí)有清道夫受體B1(scavenger receptor class B type I，SR-B1)受體變異的人患冠心病的風(fēng)險(xiǎn)明顯增加[6]。HDL-C的水平與冠心病患者死亡風(fēng)險(xiǎn)呈J型相關(guān)，即高HDL-C和低HDL-C水平均增加患者死亡率[7]。本課題組最新的研究結(jié)果也證實(shí)HDL-C水平高的鼻咽癌患者預(yù)后差，長期生存率低[8]。而大量致力于提高HDL-C水平的臨床研究發(fā)現(xiàn)HDL-C水平升高并不能降低心血管事件發(fā)生率[9-11]。相關(guān)藥物公司也停止了升高HDL-C的藥物臨床試驗(yàn)。證明是HDL功能而不是HDL-C水平起關(guān)鍵作用[12-16]。因此，提出了關(guān)于趨炎HDL和HDL功能的學(xué)說。

早在1995年，Van Lenten等[17]就發(fā)現(xiàn)在急性期反應(yīng)中，具有抗炎功能的HDL變?yōu)橼呇譎DL，失去抗LDL氧化的功能。由于載脂蛋白A-I(apolipoptrotein A-I，apoA-I)是HDL含量最高且起主要作用的蛋白質(zhì)[18]，所以，過去對apoA-I進(jìn)行了廣泛的研究。其中一個(gè)設(shè)想為是否可以通過模擬apoA-I的特殊結(jié)構(gòu)而合成模擬肽來將趨炎HDL恢復(fù)為抗炎HDL，改善HDL功能。因此，F(xiàn)ogelman等[19]基于apoA-I兩親性(親水性和疏水性)α-螺旋結(jié)構(gòu)的特點(diǎn)設(shè)計(jì)了一系列模擬apoA-I功能的短肽，這些模擬肽的功能與其結(jié)構(gòu)關(guān)系密切，現(xiàn)就apoA-I模擬肽的研究及在心血管疾病、炎癥和代謝綜合征等方面的作用作一綜述。

1 ApoA-I模擬肽結(jié)構(gòu)特點(diǎn)與代謝

Fogelman等[19]首先設(shè)計(jì)由18個(gè)氨基酸組成的apoA-I模擬肽。這種apoA-I模擬肽以苯氨酸(F)占18個(gè)氨基酸的個(gè)數(shù)分別稱為1F(只有1個(gè)苯氨酸)，2F(有2個(gè)苯氨酸), 3F(有3個(gè)苯氨酸)，以此類推?；赼poA-I的結(jié)構(gòu)特點(diǎn)，只有當(dāng)apoA-I模擬肽與脂質(zhì)的頭部基團(tuán)結(jié)合才能發(fā)揮作用[20]；而模擬肽的疏水性、電荷、疏水面積、螺旋的連接角和氨基酸組成及其界面方向性是決定其生物特性的主要因素[21-22]。3F-2和3F-14的氨基酸組成一致，但由于3F-2具有膜表面寡聚化程度更高，對氧化磷脂的親和力更強(qiáng)，以及其芳香族側(cè)鏈較深地插入膽固醇磷脂膜內(nèi)等特點(diǎn)，3F-2比3F-14功能更強(qiáng)大[23-24]。模擬肽經(jīng)脂肪族氨基酸、各類磷脂修飾或以一定方式將多個(gè)肽串聯(lián)起來后，其抗動(dòng)脈粥樣硬化效應(yīng)可能得以增強(qiáng)[25-28]。最后發(fā)現(xiàn)4F可以明顯將趨炎HDL恢復(fù)為抗炎HDL，改善HDL功能和抑制動(dòng)脈粥樣硬化形成[29]。

氯硝柳胺(本身不抑制胰蛋白酶活性)可與L-4F(由左旋氨基酸組成，所以L表示)緊密結(jié)合而使L-4F抵抗胰蛋白酶的消化[30]。盡管相同劑量的D-4F(由右旋氨基酸組成，所以以D表示)在皮下注射時(shí)的血藥濃度均高于口服，但2者的抗炎及抗主動(dòng)脈粥樣硬化效果相當(dāng)，其經(jīng)糞便排泄的總量也是相似的。提示胃腸道可能是apoA-I模擬肽發(fā)揮作用的主要位點(diǎn)[31]?？紤]到要大劑量的4F才有很好的抗動(dòng)脈粥樣硬化的效果，這樣成本很貴。設(shè)計(jì)出可以通過轉(zhuǎn)基因西紅柿擴(kuò)增的6F，口服給予低密度脂蛋白受體敲除(low density lipoprotein receptor null，LDLr-/-)小鼠6F后，發(fā)現(xiàn)完整的6F出現(xiàn)在小腸而不是血漿，并降低小腸的溶血磷脂酸(Lysophosphatidic acid，LPA)水平，再次提示胃腸道可能是apoA-I模擬肽發(fā)揮作用的主要位點(diǎn)[32]。另外，也有研究發(fā)現(xiàn)模擬肽FAMP可被血管的硬化斑塊吸收[33]。

2 ApoA-I模擬肽對心血管疾病的影響

ApoA-I模擬肽可增強(qiáng)卵磷脂-膽固醇?；D(zhuǎn)移酶活性，促進(jìn)pre-βHDL形成并加速HDL介導(dǎo)的膽固醇逆轉(zhuǎn)運(yùn)[34-35]。早在2003年，本課題組首先在LDLr-/-和鐮狀細(xì)胞疾病等小鼠模型中開展了一系列研究，發(fā)現(xiàn)L-4F可抑制LDL誘導(dǎo)的氧自由基(superoxide anion，O2-)生成以及黃嘌呤氧化酶結(jié)合到肺動(dòng)脈內(nèi)皮，改善eNOS依賴的血管舒張功能，減少動(dòng)脈粥樣硬化斑塊，而對血漿脂蛋白膽固醇水平?jīng)]有影響[36]。Navab等[37]報(bào)道D-4F能在不改變血漿總膽固醇或HDL水平的情況下發(fā)揮抗動(dòng)脈粥樣硬化效應(yīng)，但對已形成的斑塊無影響[38]。我們體外證實(shí)L-4F預(yù)處理可抑制LDL誘導(dǎo)eNOS脫偶聯(lián)以及一氧化氮(nitric oxide, NO)和O2-的失衡。L-4F本身對O2-沒有影響，但增加了NO的產(chǎn)生[39]。隨后，我們在LDLr-/-/apoA-I-/-雙敲小鼠模型中，證實(shí)D-4F只有在apoA-I存在的情況下才能發(fā)揮降低血管壁厚度的作用[40]；而代謝譜研究發(fā)現(xiàn)D-4F可通過降低血漿磷脂代謝物，尤其是長鏈溶血磷脂酰膽堿從而抑制動(dòng)脈粥樣硬化[41]。

ApoA-I模擬肽可改善硬皮病Tsk-/+小鼠eNOS依賴的血管舒張和心肌的血管新生潛能[42]，以及抑制心肌細(xì)胞的凋亡和降低左室后壁厚度[43]。在新西蘭白兔和小鼠主動(dòng)脈瓣狹窄模型中，apoA-I模擬肽能顯著增加主動(dòng)脈瓣口面積，降低主動(dòng)脈根部的膠原含量和瓣膜鈣化[44-45]。

CER-001是一種新型的重組人apoA-I與磷脂的復(fù)合物。在體外細(xì)胞和小鼠模型中，CER-001促進(jìn)了膽固醇清除，并抑制動(dòng)脈粥樣硬化斑塊的發(fā)展[46]。在臨床試驗(yàn)方面，CER-001在家族性高膽固醇血癥純合子患者和家族性低α脂蛋白血癥患者中，均顯示出促進(jìn)apoA-I和HDL形成、抗炎、抗動(dòng)脈粥樣硬化的效應(yīng)[47-48]。但一項(xiàng)在美國、荷蘭、加拿大等51個(gè)中心進(jìn)行的RCT試驗(yàn)，發(fā)現(xiàn)CER-001對動(dòng)脈粥樣硬化無影響[49]。

3 ApoA-I模擬肽對感染、炎癥和氧化損傷的影響

在人肺泡Ⅱ型細(xì)胞系A(chǔ)549和LDLr-/-小鼠，D-4F下調(diào)了流感病毒感染后血漿炎癥指標(biāo)和肺的病毒滴度，以及抑制了巨噬細(xì)胞的遷移、浸潤[50-51]。在施行盲腸結(jié)扎穿孔的SD大鼠，4F逆轉(zhuǎn)了血漿脂蛋白的紊亂，改善了心腎功能，降低了炎癥反應(yīng)和死亡率[52-53]。

在一組冠心病及其等危癥的患者中，口服D-4F可安全有效地改善HDL的抗炎性，從而抑制LDL誘導(dǎo)的單核細(xì)胞趨化活性[54]。但在另外的研究中，L-4F雖在體外改善了HDL功能，但并沒有降低冠心病患者的HDL炎癥指數(shù)，相反，增高了高敏C反應(yīng)蛋白的水平[55]。

在頸動(dòng)脈結(jié)扎小鼠和新西蘭白兔中，apoA-I模擬肽可抑制血管內(nèi)膜增生和局部炎癥分子的表達(dá)；在體外培養(yǎng)細(xì)胞和大鼠中，也可有效抑制脂多糖或TNF-α誘導(dǎo)的炎癥反應(yīng)和血流動(dòng)力學(xué)紊亂[56-60]。模擬肽可改善LDLr-/-、狼瘡小鼠的腎組織炎癥，減少蛋白尿、氧化脂質(zhì)和骨質(zhì)疏松[61-63]。而在腎切除后大鼠，L-4F可抑制促動(dòng)脈粥樣硬化信號(hào)通路分子的表達(dá)[64]。在體外將血液透析患者血漿與4F孵育，其LDL的趨炎活性下降，HDL抗炎活性升高[65-66]。在膠原誘導(dǎo)性關(guān)節(jié)炎大鼠中，D-4F+普伐他汀可顯著改善關(guān)節(jié)炎的臨床嚴(yán)重程度評分和關(guān)節(jié)的破壞性表現(xiàn)，降低血漿細(xì)胞因子/趨化因子水平和增強(qiáng)HDL的抗炎活性[67]。在LDLr-/-、APP/PS1雙轉(zhuǎn)基因敲除小鼠中，D-4F通過抑制炎癥和β淀粉樣蛋白沉積，從而改善認(rèn)知功能[68-69]。L-4F可降低高脂喂養(yǎng)的小鼠血漿的氧化標(biāo)志物，并改善了頸動(dòng)脈內(nèi)皮的愈合能力[70]。

4 ApoA-I模擬肽對代謝綜合征的影響

在Ⅰ型糖尿病模型中，D-4F降低了鏈脲霉素誘導(dǎo)的SD大鼠的氧化蛋白和氧化LDL的含量，抑制了循環(huán)內(nèi)皮細(xì)胞脫落和O2-產(chǎn)生，增強(qiáng)了血管的保護(hù)功能[71-72]。而在鏈脲霉素誘導(dǎo)的ApoE敲除小鼠中，D-4F抑制了動(dòng)脈粥樣硬化斑塊形成，并降低了血漿類花生四烯酸物質(zhì)水平[73]。在Ⅱ型糖尿病模型方面，L-4F在不改變ob/ob小鼠食物攝入的情況下，可減少內(nèi)臟和皮下的脂肪含量，降低血漿炎癥因子水平和增加胰島素的敏感性，從而降低了葡萄糖和胰島素的水平。其左心室功能也得到改善[74-75]。而在轉(zhuǎn)基因小鼠模型中，D-4F可取得與過表達(dá)人apoA-I基因相當(dāng)?shù)男Ч?，均顯著減少了白色脂肪含量和略提高了胰島素敏感性；其機(jī)制可能在于促進(jìn)解偶聯(lián)蛋白-1的表達(dá)和腺苷酸活化蛋白激酶的磷酸化[76]。

5 ApoA-I模擬肽對腫瘤的影響

D-4F抑制了卵巢癌細(xì)胞系(小鼠和人)的活性和增殖，改善其抗氧化狀態(tài)，并在C57BL/6J小鼠移植腫瘤模型中得以證實(shí)，這可能是通過上調(diào)錳超氧化物歧化酶的表達(dá)和降低LPA、低氧誘導(dǎo)因子-1α的水平實(shí)現(xiàn)的[77-79]。在誘導(dǎo)性和自發(fā)性結(jié)腸癌中，L-4F和G*(apoJ模擬肽)均有效抑制了小鼠結(jié)腸腺癌細(xì)胞的活性和增殖，降低了LPA的水平，以及息肉的大小和數(shù)目[80]。

6 總結(jié)

綜上所述，apoA-I模擬肽基于其結(jié)構(gòu)特點(diǎn)而發(fā)揮一系列保護(hù)效應(yīng)，主要包括抗心血管疾病，抗感染、炎癥和氧化損傷，改善代謝綜合征和抗癌。但apoA-I模擬肽由于其高昂的成本而極大地限制了它的實(shí)際應(yīng)用。未來若能降低其成本，可有望推動(dòng)其生產(chǎn)和進(jìn)一步的臨床研究，并最終使靶標(biāo)人群受益。

[1] Di Angelantonio E, Sarwar N, Perry P, et al. Major lipids, apolipoproteins, and risk of vascular disease.[J]. JAMA,2009,302(18):1993-2000.

[2] Robbesyn F, Garcia V, Auge N, et al. HDL counterbalance the proinflammatory effect of oxidized LDL by inhibiting intracellular reactive oxygen species rise, proteasome activation, and subsequent NF-kappa B activation in smooth muscle cells[J]. FASEB J,2003,17(2):743.

[3] Miura S, Fujino M, Matsuo Y, et al. High density lipoprotein-induced angiogenesis requires the activation of Ras/MAP kinase in human coronary artery endothelial cells[J]. Arterioscl Throm Vas,2003,23(5):802-808.

[4] Yuhanna IS, Zhu Y, Cox BE, et al. High-density lipoprotein binding to scavenger receptor-BI activates endothelial nitric oxide synthase[J]. Nat Med,2001,7(7):853-857.

[5] Brewer HB. Focus on high-density lipoproteins in reducing cardiovascular risk[J]. Am Heart J,2004,148S(1):S14-S18.

[6] Zanoni P, Khetarpal SA, Larach DB, et al. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease[J]. Science,2016,351(6278):1166-1171.

[7] Ding D, Li X, Qiu J, et al. Serum lipids, apolipoproteins, and mortality among coronary artery disease patients[J]. Biomed Res Int,2014,2014:709756.

[8] Liu YY, Lin SJ, Chen YY, et al. High-density lipoprotein cholesterol as a predictor of poor survival in patients with nasopharyngeal carcinoma[J]. Oncotarget,2016,7(28):42978-42987.

[9] Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome[J]. N Engl J Med,2012,367(22):2089-2099.

[10] Guyton JR, Slee AE, Anderson T, et al. Relationship of lipoproteins to cardiovascular events: the AIM-HIGH Trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes)[J]. J Am Coll Cardiol,2013,62(17):1580-1584.

[11] Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events[J]. N Engl J Med,2007,357(21):2109-2122.

[12] Brinck JW, Thomas A, Lauer E, et al. Diabetes mellitus is associated with reduced high-density lipoprotein Sphingosine-1-phosphate content and impaired high-density lipoprotein cardiac cell protection[J]. Arterioscler Thromb Vasc Biol,2016,36(5):817-824.

[13] Rosenson RS, Brewer HJ, Ansell BJ, et al. Dysfunctional HDL and atherosclerotic cardiovascular disease[J]. Nat Rev Cardiol,2016,13(1):48-60.

[14] Chang FJ, Yuan HY, Hu XX, et al. High density lipoprotein from patients with valvular heart disease uncouples endothelial nitric oxide synthase[J]. J Mol Cell Cardiol,2014,74:209-219.

[15] Rader DJ, Tall AR. The not-so-simple HDL story: Is it time to revise the HDL cholesterol hypothesis?[J]. Nat Med,2012,18(9):1344-1346.

[16] van Capelleveen JC, Brewer HB, Kastelein JJ, et al. Novel therapies focused on the high-density lipoprotein particle[J]. Circ Res,2014,114(1):193-204.

[17] Van Lenten BJ, Hama SY, de Beer FC, et al. Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response. Loss of protective effect of HDL against LDL oxidation in aortic wall cell cocultures[J]. J Clin Invest,1995,96(6):2758-2767.

[18] Rached FH, Chapman MJ, Kontush A. HDL particle subpopulations: Focus on biological function[J]. Biofactors,2015,41(2):67-77.

[19] Garber DW, Datta G, Chaddha M, et al. A new synthetic class A amphipathic peptide analogue protects mice from diet-induced atherosclerosis[J]. J Lipid Res,2001,42(4):545-552.

[20] Anantharamaiah GM, Mishra VK, Garber DW, et al. Structural requirements for antioxidative and anti-inflammatory properties of apolipoprotein A-I mimetic peptides[J]. J Lipid Res,2007,48(9):1915-1923.

[21] D’souza W, Stonik JA, Murphy A, et al. Structure/function relationships of apolipoprotein a-I mimetic peptides: implications for antiatherogenic activities of high-density lipoprotein[J]. Circ Res,2010,107(2):217-227.

[22] Nayyar G, Mishra VK, Handattu SP, et al. Sidedness of interfacial arginine residues and anti-atherogenicity of apolipoprotein A-I mimetic peptides[J]. J Lipid Res,2012,53(5):849-858.

[23] Epand RM, Epand RF, Sayer BG, et al. Two homologous apolipoprotein AI mimetic peptides. Relationship between membrane interactions and biological activity[J]. J Biol Chem,2004,279(49):51404-51414.

[24] Van Lenten BJ, Wagner AC, Jung CL, et al. Anti-inflammatory apoA-I-mimetic peptides bind oxidized lipids with much higher affinity than human apoA-I[J]. J Lipid Res,2008,49(11):2302-2311.

[25] Amar MJ, D’souza W, Turner S, et al. 5A apolipoprotein mimetic peptide promotes cholesterol efflux and reduces atherosclerosis in mice[J]. J Pharmacol Exp Ther,2010,334(2):634-641.

[26] Iwata A, Miura S, Zhang B, et al. Antiatherogenic effects of newly developed apolipoprotein A-I mimetic peptide/phospholipid complexes against aortic plaque burden in Watanabe-heritable hyperlipidemic rabbits[J]. Atherosclerosis,2011,218(2):300-307.

[27] Song X, Fischer P, Chen X, et al. An apoA-I mimetic peptide facilitates off-loading cholesterol from HDL to liver cells through scavenger receptor BI[J]. Int J Biol Sci,2009,5(7):637-646.

[28] Zhao Y, Black AS, Bonnet DJ, et al. In vivo efficacy of HDL-like nanolipid particles containing multivalent peptide mimetics of apolipoprotein A-I[J]. J Lipid Res,2014,55(10):2053-2063.

[29] Navab M, Anantharamaiah GM, Hama S, et al. Oral administration of an Apo A-I mimetic Peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol[J]. Circulation,2002,105(3):290-292.

[30] Navab M, Ruchala P, Waring AJ, et al. A novel method for oral delivery of apolipoprotein mimetic peptides synthesized from all L-amino acids[J]. J Lipid Res,2009,50(8):1538-1547.

[31] Navab M, Reddy S T, Anantharamaiah G M, et al. Intestine may be a major site of action for the apoA-I mimetic peptide 4F whether administered subcutaneously or orally[J]. J Lipid Res,2011,52(6):1200-1210.

[32] Chattopadhyay A, Navab M, Hough G, et al. A novel approach to oral apoA-I mimetic therapy[J]. J Lipid Res,2013,54(4):995-1010.

[33] Kawachi E, Uehara Y, Hasegawa K, et al. Novel molecular imaging of atherosclerosis with gallium-68-labeled apolipoprotein A-I mimetic peptide and positron emission tomography[J]. Circ J,2013,77(6):1482-1489.

[34] Chen X, Burton C, Song X, et al. An apoA-I mimetic peptide increases LCAT activity in mice through increasing HDL concentration[J]. Int J Biol Sci,2009,5(5):489-499.

[35] Navab M, Anantharamaiah GM, Reddy ST, et al. Oral D-4F causes formation of pre-beta high-density lipoprotein and improves high-density lipoprotein-mediated cholesterol efflux and reverse cholesterol transport from macrophages in apolipoprotein E-null mice[J]. Circulation,2004,109(25):3215-3220.

[36] Ou J, Ou Z, Jones DW, et al. L-4F, an apolipoprotein A-1 mimetic, dramatically improves vasodilation in hypercholesterolemia and sickle cell disease[J]. Circulation,2003,107(18):2337-2341.

[37] Navab M, Anantharamaiah GM, Hama S, et al. Oral administration of an ApoA-I mimetic Peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol[J]. Circulation,2002,105(3):290-292.

[38] Li X, Chyu KY, Faria NJ, et al. Differential effects of apolipoprotein A-I-mimetic peptide on evolving and established atherosclerosis in apolipoprotein E-null mice[J]. Circulation,2004,110(12):1701-1705.

[39] Ou Z, Ou J, Ackerman AW, et al. L-4F, an apolipoprotein A-1 mimetic, restores nitric oxide and superoxide anion balance in low-density lipoprotein-treated endothelial cells[J]. Circulation,2003,107(11):1520-1524.

[40] Ou J, Wang J, Xu H, et al. Effects of D-4F on vasodilation and vessel wall thickness in hypercholesterolemic LDL receptor-null and LDL receptor/apolipoprotein A-I double-knockout mice on Western diet[J]. Circ Res,2005,97(11):1190-1197.

[41] Ou ZJ, Li L, Liao XL, et al. Apolipoprotein A-I mimetic peptide inhibits atherosclerosis by altering plasma metabolites in hypercholesterolemia[J]. Am J Physiol Endocrinol Metab,2012,303(6):E683-E694.

[42] Weihrauch D, Xu H, Shi Y, et al. Effects of D-4F on vasodilation, oxidative stress, angiostatin, myocardial inflammation, and angiogenic potential in tight-skin mice[J]. Am J Physiol Heart Circ Physiol,2007,293(3):H1432-H1441.

[43] Xu H, Krolikowski JG, Jones DW, et al. 4F decreases IRF5 expression and activation in hearts of tight skin mice[J]. PLoS One,2012,7(12):e52046.

[44] Busseuil D, Shi Y, Mecteau M, et al. Regression of aortic valve stenosis by ApoA-I mimetic peptide infusions in rabbits[J]. Br J Pharmacol,2008,154(4):765-773.

[45] Trapeaux J, Busseuil D, Shi Y, et al. Improvement of aortic valve stenosis by ApoA-I mimetic therapy is associated with decreased aortic root and valve remodelling in mice[J]. Br J Pharmacol,2013,169(7):1587-1599.

[46] Tardy C, Goffinet M, Boubekeur N, et al. CER-001, a HDL-mimetic, stimulates the reverse lipid transport and atherosclerosis regression in high cholesterol diet-fed LDL-receptor deficient mice[J]. Atherosclerosis,2014,232(1):110-118.

[47] Hovingh GK, Smits LP, Stefanutti C, et al. The effect of an apolipoprotein A-I-containing high-density lipoprotein-mimetic particle (CER-001) on carotid artery wall thickness in patients with homozygous familial hypercholesterolemia: The Modifying Orphan Disease Evaluation (MODE) study[J]. Am Heart J,2015,169(5):736-742.

[48] Kootte RS, Smits LP, van der Valk FM, et al. Effect of open-label infusion of an apoA-I-containing particle (CER-001) on RCT and artery wall thickness in patients with FHA[J]. J Lipid Res,2015,56(3):703-712.

[49] Tardif JC, Ballantyne CM, Barter P, et al. Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: a randomized trial[J]. Eur Heart J,2014,35(46):3277-3286.

[50] Van Lenten BJ, Wagner AC, Anantharamaiah GM, et al. Influenza infection promotes macrophage traffic into arteries of mice that is prevented by D-4F, an apolipoprotein A-I mimetic peptide[J]. Circulation,2002,106(9):1127-1132.

[51] Van Lenten BJ, Wagner AC, Navab M, et al. D-4F, an apolipoprotein A-I mimetic peptide, inhibits the inflammatory response induced by influenza A infection of human type II pneumocytes[J]. Circulation,2004,110(20):3252-3258.

[52] Zhang Z, Datta G, Zhang Y, et al. Apolipoprotein A-I mimetic peptide treatment inhibits inflammatory responses and improves survival in septic rats[J]. Am J Physiol Heart Circ Physiol,2009,297(2):H866-H873.

[53] Moreira RS, Irigoyen M, Sanches TR, et al. Apolipoprotein A-I mimetic peptide 4F attenuates kidney injury, heart injury, and endothelial dysfunction in sepsis[J]. Am J Physiol Regul Integr Comp Physiol,2014,307(5):R514-R524.

[54] Bloedon LT, Dunbar R, Duffy D, et al. Safety, pharmacokinetics, and pharmacodynamics of oral apoA-I mimetic peptide D-4F in high-risk cardiovascular patients[J]. J Lipid Res,2008,49(6):1344-1352.

[55] Watson CE, Weissbach N, Kjems L, et al. Treatment of patients with cardiovascular disease with L-4F, an apo-A1 mimetic, did not improve select biomarkers of HDL function[J]. J Lipid Res,2011,52(2):361-373.

[56] Du L, Qu X, Zheng H, et al. Reverse apolipoprotein A-I mimetic peptide R-D4F inhibits neointimal formation following carotid artery ligation in mice[J]. Am J Pathol,2013,182(5):1932-1939.

[57] Di Bartolo BA, Nicholls SJ, Bao S, et al. The apolipoprotein A-I mimetic peptide ETC-642 exhibits anti-inflammatory properties that are comparable to high density lipoproteins[J]. Atherosclerosis,2011,217(2):395-400.

[58] White CR, Smythies LE, Crossman DK, et al. Regulation of pattern recognition receptors by the apolipoprotein A-I mimetic peptide 4F[J]. Arterioscler Thromb Vasc Biol,2012,32(11):2631-2639.

[59] Tabet F, Remaley AT, Segaliny AI, et al. The 5A apolipoprotein A-I mimetic peptide displays antiinflammatory and antioxidant properties in vivo and in vitro[J]. Arterioscler Thromb Vasc Biol,2010,30(2):246-252.

[60] Dai L, Datta G, Zhang Z, et al. The apolipoprotein A-I mimetic peptide 4F prevents defects in vascular function in endotoxemic rats[J]. J Lipid Res,2010,51(9):2695-2705.

[61] Buga GM, Frank JS, Mottino GA, et al. D-4F reduces EO6 immunoreactivity, SREBP-1c mRNA levels, and renal inflammation in LDL receptor-null mice fed a Western diet[J]. J Lipid Res,2008,49(1):192-205.

[62] Vaziri ND, Kim HJ, Moradi H, et al. Amelioration of nephropathy with apoA-1 mimetic peptide in apoE-deficient mice[J]. Nephrol Dial Transplant,2010,25(11):3525-3534.

[63] Woo JM, Lin Z, Navab M, et al. Treatment with apolipoprotein A-1 mimetic peptide reduces lupus-like manifestations in a murine lupus model of accelerated atherosclerosis[J]. Arthritis Res Ther,2010,12(3):R93.

[64] Vaziri ND, Bai Y, Yuan J, et al. ApoA-1 mimetic peptide reverses uremia-induced upregulation of pro-atherogenic pathways in the aorta[J]. Am J Nephrol,2010,32(3):201-211.

[65] Vaziri ND, Moradi H, Pahl MV, et al. In vitro stimulation of HDL anti-inflammatory activity and inhibition of LDL pro-inflammatory activity in the plasma of patients with end-stage renal disease by an apoA-1 mimetic peptide[J]. Kidney Int,2009,76(4):437-444.

[66] Kaysen GA. Potential restoration of HDL function with apolipoprotein A-I mimetic peptide in end-stage renal disease[J]. Kidney Int,2009,76(4):359-361.

[67] Charles-Schoeman C, Banquerigo ML, Hama S, et al. Treatment with an apolipoprotein A-1 mimetic peptide in combination with pravastatin inhibits collagen-induced arthritis[J]. Clin Immunol,2008,127(2):234-244.

[68] Handattu SP, Garber DW, Monroe CE, et al. Oral apolipoprotein A-I mimetic peptide improves cognitive function and reduces amyloid burden in a mouse model of Alzheimer’s disease[J]. Neurobiol Dis,2009,34(3):525-534.

[69] Buga GM, Frank JS, Mottino GA, et al. D-4F decreases brain arteriole inflammation and improves cognitive performance in LDL receptor-null mice on a Western diet[J]. J Lipid Res,2006,47(10):2148-2160.

[70] Rosenbaum MA, Chaudhuri P, Abelson B, et al. Apolipoprotein A-I mimetic peptide reverses impaired arterial healing after injury by reducing oxidative stress[J]. Atherosclerosis,2015,241(2):709-715.

[71] Kruger AL, Peterson S, Turkseven S, et al. D-4F induces heme oxygenase-1 and extracellular superoxide dismutase, decreases endothelial cell sloughing, and improves vascular reactivity in rat model of diabetes[J]. Circulation,2005,111(23):3126-3134.

[72] Peterson SJ, Husney D, Kruger AL, et al. Long-term treatment with the apolipoprotein A1 mimetic peptide increases antioxidants and vascular repair in type I diabetic rats[J]. J Pharmacol Exp Ther,2007,322(2):514-520.

[73] Morgantini C, Imaizumi S, Grijalva V, et al. Apolipoprotein A-I mimetic peptides prevent atherosclerosis development and reduce plaque inflammation in a murine model of diabetes[J]. Diabetes,2010,59(12):3223-3228.

[74] Peterson SJ, Drummond G, Kim DH, et al. L-4F treatment reduces adiposity, increases adiponectin levels, and improves insulin sensitivity in obese mice[J]. J Lipid Res,2008,49(8):1658-1669.

[75] Vecoli C, Cao J, Neglia D, et al. Apolipoprotein A-I mimetic peptide L-4F prevents myocardial and coronary dysfunction in diabetic mice[J]. J Cell Biochem,2011,112(9):2616-2626.

[76] Ruan X, Li Z, Zhang Y, et al. Apolipoprotein A-I possesses an anti-obesity effect associated with increase of energy expenditure and up-regulation of UCP1 in brown fat[J]. J Cell Mol Med,2011,15(4):763-772.

[77] Ganapathy E, Su F, Meriwether D, et al. D-4F, an apoA-I mimetic peptide, inhibits proliferation and tumorigenicity of epithelial ovarian cancer cells by upregulating the antioxidant enzyme MnSOD[J]. Int J Cancer,2012,130(5):1071-1081.

[78] Su F, Kozak KR, Imaizumi S, et al. Apolipoprotein A-I (apoA-I) and apoA-I mimetic peptides inhibit tumor development in a mouse model of ovarian cancer[J]. Proc Natl Acad Sci U S A,2010,107(46):19997-20002.

[79] Gao F, Chattopadhyay A, Navab M, et al. Apolipoprotein A-I mimetic peptides inhibit expression and activity of hypoxia-inducible factor-1alpha in human ovarian cancer cell lines and a mouse ovarian cancer model[J]. J Pharmacol Exp Ther,2012,342(2):255-262.

[80] Su F, Grijalva V, Navab K, et al. HDL mimetics inhibit tumor development in both induced and spontaneous mouse models of colon cancer[J]. Mol Cancer Ther,2012,11(6):1311-1319.

(編校：吳茜)

Research advances on the apolipoptrotein A-I mimetic peptides

LIU Xiang1,2,4, OU Zhi-jun3,4, LI Yan1,2,4, OU Jing-song1,2,4,5

(1.Division of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; 2.The key Laboratory of Assisted Circulation, Ministry of Health, Zhongshan School of Medicine, SYSU, Guangzhou 510275, China; 3.Division of Hypertension and Vascular Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; 4.National and Guangdong Province Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou 510080, China; 5.Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine of Sun Yat-sent University, Guangzhou 510080, China)

High density lipoprotein cholesterol (HDL-C) has

extensive attention because of its cardiovascular protective effects. Recent studies showed that HDL could promote reverse cholesterol transport (RCT), be anti-inflammatory and antioxidant, and induce angiogenesis. Apolipoptrotein A-I (apoA-I), the most abundant protein of HDL, plays a pivotal role in the HDL mediated-functional activities. Short peptides based on the amphiphilic alpha helix structure of apoA-I have been designed and aimed at imitating the function of apoA-I. The function and metabolism of these mimetic peptides depend on their amino acids component and sequence, and have been proved to exert protection in against cardiovascular disease, infection, inflammation and oxidative damage, metabolic syndrome and tumor. Clinical trials confirmed their benefits, but high cost put them out of the practical applications..

apolipoptroteinA-I; cardiovascular disease; inflammation; metabolic syndrome

10.3969/j.issn.1005-1678.2016.12.005

教育部長江學(xué)者獎(jiǎng)勵(lì)計(jì)劃項(xiàng)目；國家杰出青年科學(xué)基金(81325001)；國家自然科學(xué)基金(81170271, 81370370)；廣東省高等學(xué)校高層次人才項(xiàng)目(珠江學(xué)者計(jì)劃)；國家臨床重點(diǎn)專科建設(shè)項(xiàng)目；科技部國際合作專項(xiàng)(2015DFA31070)；廣東省自然科學(xué)基金研究團(tuán)隊(duì)項(xiàng)目(2015A030312009)。

劉湘，博士在讀，研究方向：心血管，E-mail：liux69@mail2.sysu.edu.cn；區(qū)景松，通信作者，男，博士，教授、主任醫(yī)師，研究方向：心血管，E-mail：oujs@mail.sysu.edu.cn。

R541.4

A