SIRT3與細(xì)胞代謝及心血管疾病的相關(guān)性

曹麗娟，劉昕訸，查晴，宋倩，楊克，劉艷

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SIRT3與細(xì)胞代謝及心血管疾病的相關(guān)性

曹麗娟，劉昕訸，查晴，宋倩，楊克，劉艷

上海交通大學(xué)醫(yī)學(xué)院附屬瑞金醫(yī)院心血管內(nèi)科，上海 200025

蛋白去乙?；冈诩?xì)胞生理過(guò)程中發(fā)揮著極為重要的作用。人蛋白去乙?；赴℉DACⅠ、HDACⅡ、HDACⅢ和HDACⅣ4個(gè)家族。其中第Ⅲ類即Sir2(Silent information regulator 2)家族包括7個(gè)成員——SIRT1~ SIRT7，每個(gè)成員都具有不同的細(xì)胞定位，并且發(fā)揮不同的生物學(xué)功能。作為主要定位于線粒體的組蛋白去乙?；?，SIRT3不僅調(diào)節(jié)細(xì)胞的能量代謝，并在細(xì)胞凋亡、腫瘤生長(zhǎng)和一些疾病中發(fā)揮作用。文章綜述了SIRT3在細(xì)胞代謝中的生物學(xué)功能以及其在心血管疾病中的研究進(jìn)展。

SIRT3；組蛋白去乙?；?；細(xì)胞代謝；心血管疾病

蛋白質(zhì)乙?；?去乙酰化是一種非常重要的翻譯后修飾，也是調(diào)節(jié)酶活性以適應(yīng)細(xì)胞代謝和能量改變的一個(gè)重要方式。在酵母(Meyen ex Hansen)中，蛋白去乙酰化酶分為Rpd3(Reduced potassium dependency 3)、Hda1(Histone deacetylase 1)和Sir2(Silent information regulator 2)共3個(gè)家族，根據(jù)對(duì)酵母種系發(fā)育中組蛋白去乙?；?Histone deacetylases, HDACs)結(jié)構(gòu)的同源性分析[1]，真核生物HDACs可分為4類，即HDACⅠ~Ⅳ類[2]。Ⅰ類HDACs包括HDAC1~3和HDAC8，與酵母Rpd3蛋白具有同源性，主要分布于細(xì)胞核中，并在各類組織細(xì)胞中廣泛表達(dá)。Ⅱ類HDACs分為Ⅱa和Ⅱb，與酵母Hda1蛋白同源，其中Ⅱa包括HDAC4、HDAC5、HDAC7和HDAC9，Ⅱb包括HDAC6和HDACl0。Ⅱ類HDACs在細(xì)胞核和細(xì)胞質(zhì)均有分布，主要在心臟、肺、骨骼肌中表達(dá)。Ⅱ類HDACs在細(xì)胞核、細(xì)胞質(zhì)的分布受肌細(xì)胞增強(qiáng)因子2(Myocyte enhancer factor 2, MEF2)和14-3-3蛋白調(diào)節(jié)[3]。正常情況下，MEF2與Ⅱ類HDACs結(jié)合并以復(fù)合物的形式定位于細(xì)胞核以維持細(xì)胞的穩(wěn)態(tài)；而在病理狀況下，Ⅱ類HDACs可被磷酸化并與伴侶分子14-3-3蛋白結(jié)合而滯留在細(xì)胞漿內(nèi)，同時(shí)MEF2可被磷酸化并調(diào)控相應(yīng)基因的表達(dá)，導(dǎo)致肌細(xì)胞增生[3~5]。HDAC11兼有Ⅰ類和Ⅱ類HDACs特性，單獨(dú)歸為第Ⅳ類。上述3類HDACs均為金屬蛋白酶，其酶催化中心均含有Zn2+。而Ⅲ類HDACs與酵母Sir2蛋白同源，其活性依賴于尼克酰胺腺苷酸(NAD+)，而非Zn2+[6,7]。Sir2是一類在進(jìn)化中高度保守的蛋白質(zhì)，存在于原核和真核生物中，具有NAD+蛋白活性。

Sirtuins是一類NAD+依賴性組蛋白去乙?；?，其去乙酰化作用無(wú)特異性，除組蛋白底物外，還可使非組蛋白底物去乙?；痆8~10]。哺乳動(dòng)物Sirtuins家族有7個(gè)成員(SIRTl~SIRT7)，其基因定位、組織表達(dá)、細(xì)胞定位、酶活性、主要作用底物及功能方面各不相同(表1)[11~49]。SIRT1~SIRT7家族成員在衰老、基因沉默、細(xì)胞代謝、細(xì)胞生長(zhǎng)和凋亡以及晝夜節(jié)律等方面起重要的調(diào)節(jié)作用[11]。

以往針對(duì)Sirtuins家族的研究主要集中于SIRT1，主要與細(xì)胞生存[16,22,42]、細(xì)胞代謝[47]、炎癥[48]、氧化應(yīng)激[14]、衰老及衰老相關(guān)性疾病(如動(dòng)脈粥樣硬化及糖尿病等)[28,37]密切相關(guān)。目前，其他成員的研究亦成為熱點(diǎn)，特別是家族重要成員SIRT3，其分布于人體多個(gè)臟器，且作用底物廣泛，主要調(diào)控細(xì)胞能量代謝、生物合成及細(xì)胞凋亡等，并與心血管疾病密切相關(guān)[17,18]。本文就SIRT3的結(jié)構(gòu)、定位、主要功能及其在心血管疾病中的臨床意義等研究進(jìn)展進(jìn)行了綜述。

1 SIRT3定位與分布

人基因位于11號(hào)染色體p15.5(11p15.5)，由21 902個(gè)堿基構(gòu)成?；蚓幋a蛋白由399個(gè)氨基酸構(gòu)成，分子量約44 kDa。其N端包含一個(gè)由25個(gè)氨基酸殘基組成的線粒體定位信號(hào)肽，在線粒體基質(zhì)中被肽酶識(shí)別剪切后，形成一個(gè)28 kDa大小的成熟酶蛋白[50,51]。兩個(gè)可變剪接轉(zhuǎn)錄變體編碼兩種不同蛋白亞型，分別為1~399氨基酸(全長(zhǎng)型SIRT3)和142~399氨基酸(成熟型SIRT3)。

Cooper等[52]認(rèn)為，全長(zhǎng)型SIRT3僅定位于線粒體。但隨著研究的不斷深入，Iwahara等[53]發(fā)現(xiàn)，細(xì)胞在應(yīng)激刺激后，全長(zhǎng)型SIRT3可被酶剪切為成熟SIRT3[53,54]。由于缺乏線粒體定位信號(hào)，成熟型SIRT3非特異性地分布于線粒體或細(xì)胞質(zhì)中，甚至出現(xiàn)于細(xì)胞核中。研究發(fā)現(xiàn)，無(wú)論是定位在線粒體、細(xì)胞質(zhì)還是細(xì)胞核，SIRT3均具去乙?；富钚訹41]。因此，SIRT3的去乙?；δ芸赡芘c其細(xì)胞定位無(wú)關(guān)。

但是，SIRT3分布具有明顯的組織特異性，并與器官代謝活性相關(guān)。代謝活性越強(qiáng)的器官，如肝臟、棕色脂肪組織、心臟及腎臟等，其SIRT3表達(dá)也越高。研究表明，在低溫環(huán)境中，機(jī)體通過(guò)增強(qiáng)棕色脂肪細(xì)胞中的SIRT3表達(dá)，去乙?；⒓せ罱馀悸?lián)蛋白活性，提高機(jī)體代謝率以維持體溫[51]。同樣，運(yùn)動(dòng)、節(jié)食和能量限制等均可增強(qiáng)SIRT3表達(dá)活性；而長(zhǎng)期高脂飲食會(huì)使其表達(dá)降低[7,17,21]。雖然SIRT3組織特異性分布的具體機(jī)制尚不清楚，但是其高表達(dá)于高能量代謝器官，提示其與細(xì)胞能量代謝調(diào)控密切相關(guān)。

2 SIRT3功能

線粒體的主要功能為能量合成，同時(shí)還具有調(diào)節(jié)活性氧(Reactive oxygen species, ROS)生成、細(xì)胞代謝(如膽固醇、激素合成等)及細(xì)胞凋亡等生物活性。SIRT3作為線粒體中主要的去乙?；?，可調(diào)節(jié)細(xì)胞能量合成和線粒體生理活性，同時(shí)參與調(diào)控細(xì)胞生存維持所需生物分子(如蛋白質(zhì)及脂質(zhì)等)合成等作用[17,55]。SIRT3參與幾乎所有與機(jī)體細(xì)胞代謝相關(guān)信號(hào)通路的調(diào)控，如ROS產(chǎn)生和清除[56]、三羧酸循環(huán)(Tricarboxylic acid cycle, TAC)[17,18,57~59]、脂肪酸氧化(Fatty acid metabolism, FAM)[21,51,60]、尿素循環(huán)(Urea cycle, UC)[21]、酮體生成[24,61]、蛋白質(zhì)合成[7,8]及細(xì)胞生長(zhǎng)和凋亡[20]等(圖1)。

研究表明，SIRT3表達(dá)水平及其生物活性受多種因素影響，包括：外界因素如能量限制、禁食、體溫、衰老及運(yùn)動(dòng)等[17,27,62]；內(nèi)部因素如NAD+/NADH活性變化、過(guò)氧化物酶體增值物激活受體-γ共激活因子1-α(Peroxisome proliferator-activated receptor γ coa-ctivator-1α, PGC-1α)的表達(dá)及激活、雌激素受體反應(yīng)元件(Estrogen receptor responsive element, ERRE)的激活及羥化作用和瘦素表達(dá)水平等[8,17,35,38](圖1)。

中英文對(duì)照縮表見(jiàn)附表1。

環(huán)境因素(晝夜、氣溫及應(yīng)激等)對(duì)機(jī)體的各項(xiàng)生命活動(dòng)具有非常重要的影響，往往會(huì)造成機(jī)體中臟器、細(xì)胞乃至分子的波動(dòng)，而這些影響往往與能量密切相關(guān)。但是，各項(xiàng)生命活動(dòng)均需一個(gè)相對(duì)穩(wěn)定的內(nèi)部環(huán)境，因此需要一系列基因參與其內(nèi)維持能量網(wǎng)絡(luò)的穩(wěn)態(tài)。正是基于這樣一種生命維持模式，SIRT3的表達(dá)對(duì)于外界及細(xì)胞內(nèi)多種刺激因素產(chǎn)生應(yīng)答，同時(shí)，其下游調(diào)控基因也多與能量代謝密切相關(guān)。SIRT3作為能量代謝網(wǎng)絡(luò)中一個(gè)重要環(huán)節(jié)調(diào)節(jié)機(jī)體自身能量代謝平衡，從而使得機(jī)體能夠應(yīng)對(duì)環(huán)境的變化。

2.1 SIRT3與能量代謝

能量代謝是細(xì)胞生存的基礎(chǔ)活動(dòng)，當(dāng)細(xì)胞能量需求或供給發(fā)生變化時(shí)，細(xì)胞代謝就會(huì)發(fā)生一系列調(diào)整以維持細(xì)胞生存。當(dāng)能量供應(yīng)減少(如能量限制，即在保證機(jī)體正常營(yíng)養(yǎng)需求情況下，減少機(jī)體30%~40%能量攝入)或能量需求增加(如寒冷暴露)時(shí)，一方面線粒體SIRT3通過(guò)去乙?；€粒體核糖體蛋白L10，降低50%~60%線粒體核糖體內(nèi)蛋白質(zhì)(如細(xì)胞色素C氧化酶亞基II)合成，降低葡萄糖代謝速率及與其相關(guān)的氧化磷酸化水平[8]。

另一方面，線粒體SIRT3還通過(guò)去乙?；饔迷鰪?qiáng)長(zhǎng)鏈?；o酶A脫氫酶、烯酰輔酶A水合酶、3-羥?；o酶A脫氫酶及親環(huán)素D等蛋白活性，促進(jìn)細(xì)胞脂肪酸氧化；激活羥甲戊二酰輔酶A合成酶2，促進(jìn)酮體生成；提高谷氨酸脫氫酶、乙酰輔酶A合成酶2、蘋(píng)果酸脫氫酶及琥珀酸脫氫酶等酶活性，加速細(xì)胞三羧酸循環(huán)；激活氨甲?；姿岷铣擅涪窈网B(niǎo)氨酸氨甲?；D(zhuǎn)移酶，加速尿素循環(huán)，促進(jìn)氨基酸氧化[13,14,21,24,29]。

在能量缺乏時(shí)，機(jī)體通過(guò)SIRT3上述調(diào)節(jié)作用，減少葡萄糖氧化和蛋白質(zhì)合成，提高脂肪酸、氨基酸氧化及酮體生成等過(guò)程，維持機(jī)體能量供給。同時(shí)，上述調(diào)節(jié)還能保證一些特殊器官(如大腦等)在機(jī)體葡萄糖水平降低的情況下，可通過(guò)消耗乙酰乙酸和b-羥丁酸來(lái)維持細(xì)胞的能量平衡[14,18,25,40,63]。

由此可見(jiàn)，SIRT3參與調(diào)節(jié)能量代謝的各個(gè)方面，對(duì)機(jī)體能量代謝各項(xiàng)機(jī)能起著不可替代的調(diào)控作用，通過(guò)維持機(jī)體內(nèi)能量代謝平衡，從而保護(hù)應(yīng)激條件下器官生理活性。

2.2 SIRT3與ROS

氧化應(yīng)激所導(dǎo)致的細(xì)胞內(nèi)ROS累積與心肌肥厚[20,44,64,65]、冠狀動(dòng)脈粥樣硬化[66,67]、高脂血癥[21,68]、2型糖尿病[69]、胰島素抵抗[70]、脂肪肝[7,71]、神經(jīng)退行性疾病(如年齡相關(guān)的聽(tīng)力損傷)[9,72]、阿爾茲海默病[73,74]及腫瘤[63,75~78]等疾病密切相關(guān)。

Bell等[79]認(rèn)為，線粒體SIRT3可直接去乙?；⒓せ羁寡趸蜃渝i超氧化物歧化酶(Manganese sup-eroxide dismutase, MnSOD)和異檸檬酸脫氫酶2(Isoci-trate dehydrogenase 2, IDH2)，啟動(dòng)抗氧化過(guò)程，防止ROS累積；Jacobs等[56]還發(fā)現(xiàn)，細(xì)胞核內(nèi)SIRT3可通過(guò)去乙?；瘡亩黾愚D(zhuǎn)錄因子叉形頭轉(zhuǎn)錄因子的O亞型(Forkhead box O3, FOXO3a)表達(dá)，而后者則進(jìn)一步促進(jìn)MnSOD和IDH2表達(dá)減輕氧化應(yīng)激對(duì)細(xì)胞的損傷，延緩相關(guān)疾病的發(fā)生和發(fā)展[56,79]。SIRT3通過(guò)直接和間接作用下調(diào)ROS水平，促進(jìn)一氧化碳合成酶(Endothelial nitric oxide synthase, eNOS)生成，改善血管內(nèi)皮功能，從而延緩動(dòng)脈粥樣硬化形成和進(jìn)展[80]。

但是，當(dāng)細(xì)胞內(nèi)SIRT3表達(dá)水平下降時(shí)，線粒體中的MnSOD和IDH2等抗氧化因子活性也會(huì)隨之下降，造成ROS累積，導(dǎo)致線粒體功能紊亂，從而誘發(fā)胰島素抵抗、2型糖尿病及惡性腫瘤等疾病[43,63,79,81]。其導(dǎo)致胰島素抵抗的可能機(jī)制為：伴隨SIRT3水平降低，細(xì)胞內(nèi)ROS清除作用削減，ROS在細(xì)胞內(nèi)大量累積，從而激活氧化應(yīng)激相關(guān)信號(hào)通路蛋白PKC (Protein kinase C)、S6激酶和JNK(Jun N-terminal kinase)等，下調(diào)胰島素受體底物-1(Insulin receptor substrate, IRS-1)酪氨酸磷酸化水平，降低PI3K及Akt磷酸化水平，抑制胰島素信號(hào)通路，誘發(fā)胰島素抵抗，從而導(dǎo)致與胰島素抵抗密切相關(guān)的2型糖尿病發(fā)生和發(fā)展。

SIRT3通過(guò)ROS信號(hào)通路還與腫瘤的發(fā)生發(fā)展密切相關(guān)。SIRT3表達(dá)上升可降低ROS水平，使低氧誘導(dǎo)因子-1α(Hypoxia inducible factor-1, HIF-1α)穩(wěn)定性下降，通過(guò)抑制ROS累積和HIF-1α活性從而抑制腫瘤細(xì)胞生長(zhǎng)。但是，當(dāng)SIRT3水平降低時(shí)，ROS累積增加，HIF-1α表達(dá)上調(diào)，穩(wěn)定性及活性增加，進(jìn)而誘導(dǎo)缺氧反應(yīng)蛋白(如血管內(nèi)皮生長(zhǎng)因子)的表達(dá)，加速糖酵解代謝，促進(jìn)營(yíng)養(yǎng)物質(zhì)氧化和ATP產(chǎn)生[63]，增加腫瘤細(xì)胞在缺氧環(huán)境下的適應(yīng)性，促進(jìn)腫瘤細(xì)胞增殖、新生血管生成、侵襲和遷移[43,79]。

ROS是導(dǎo)致大部分疾病發(fā)生發(fā)展的重要因素，而調(diào)節(jié)ROS累積對(duì)于疾病的發(fā)生和發(fā)展具有決定性作用，SIRT3的表達(dá)水平與ROS累積具有負(fù)相關(guān)性。在氧化應(yīng)激時(shí)，其表達(dá)具有應(yīng)激性升高的特點(diǎn)，起到保護(hù)細(xì)胞對(duì)抗氧化應(yīng)激的作用。但是，當(dāng)應(yīng)激反應(yīng)進(jìn)一步放大時(shí)，其表達(dá)大幅下降，原有的平衡調(diào)節(jié)作用喪失，相反促進(jìn)氧化應(yīng)激反應(yīng)，最終加速疾病進(jìn)展。調(diào)節(jié)SIRT3表達(dá)可有效對(duì)抗氧化應(yīng)激從而逆轉(zhuǎn)病程。

2.3 SIRT3與細(xì)胞凋亡和生長(zhǎng)

在細(xì)胞凋亡和生長(zhǎng)過(guò)程中，SIRT3具有非常復(fù)雜的生物效應(yīng)。一方面，SIRT3可通過(guò)調(diào)節(jié)Bcl-2或JNK2活性，促進(jìn)細(xì)胞凋亡[82]；另一方面，SIRT3又可通過(guò)核轉(zhuǎn)錄因子FOXO3a和Ku70信號(hào)通路，參與維持細(xì)胞生存[53,82,83]。

Allison等[82]在研究腫瘤發(fā)病機(jī)制時(shí)發(fā)現(xiàn)，敲除Bcl-2可引發(fā)細(xì)胞凋亡，但是共敲除SIRT3后，反而延緩了細(xì)胞的凋亡進(jìn)程[82,84]，提示腫瘤細(xì)胞中的SIRT3參與Bcl-2/p53凋亡信號(hào)通路。Allison等[82]研究還表明，JNK1可通過(guò)促進(jìn)SIRT3轉(zhuǎn)錄，加速JNK-2/JNK1相關(guān)的非P53依賴性凋亡。

在生理狀況下，SIRT3還可通過(guò)去乙?；孜顰ceCS2參與Bcl-2/p53誘導(dǎo)的細(xì)胞生長(zhǎng)停滯反應(yīng)。研究發(fā)現(xiàn)，敲除Bcl-2可誘導(dǎo)細(xì)胞停滯在G1期，此過(guò)程依賴于SIRT3/AceCS2，推測(cè)SIRT3/AceCS2是細(xì)胞生長(zhǎng)中不可或缺的調(diào)節(jié)因素。SIRT3可能通過(guò)該途徑延長(zhǎng)機(jī)體壽命。因此，SIRT3可能是一個(gè)長(zhǎng)壽因子[85]。

在慢性炎癥刺激等應(yīng)激情況下，SIRT3可通過(guò)以下方式參與細(xì)胞凋亡的調(diào)控：(1)MnSOD和IDH2途徑。SIRT3去乙?；疐OXO3a，提高其底物MnSOD和IDH2活性，后兩者可減少細(xì)胞內(nèi)ROS含量。線粒體SIRT3還能直接使MnSOD和IDH2蛋白去乙?；?，增強(qiáng)其抗氧化活性，減少ROS累積，從而降低ROS對(duì)細(xì)胞的損傷。(2)Ku70途徑。SIRT3去乙?；疜u70，使后者與促凋亡蛋白Bax緊密結(jié)合，阻止Bax由細(xì)胞核轉(zhuǎn)運(yùn)至線粒體，從而抑制細(xì)胞凋亡[85,86]。SIRT3通過(guò)這些途徑來(lái)維持線粒體的內(nèi)環(huán)境穩(wěn)定，以保護(hù)線粒體的正常生理功能，抑制細(xì)胞凋亡和壞死。

在生理情況下，大多數(shù)離子和溶質(zhì)都不能通過(guò)線粒體屏障，這有利于保持細(xì)胞膜內(nèi)、外兩側(cè)Ca2+離子平衡和正常的細(xì)胞膜電位以維持細(xì)胞正常生理功能。然而，隨著年齡的增長(zhǎng)，細(xì)胞內(nèi)環(huán)境的改變，如ROS和Ca2+水平升高，可誘導(dǎo)線粒體膜表面通透性轉(zhuǎn)換孔(Mitochondrial permeability transition pore, mPTP)的形成。在病理情況下，慢性低水平的應(yīng)激刺激可誘導(dǎo)線粒體上mPTP的形成，如糖尿病病人中蛋白高糖基化或高血脂氧化脂蛋白刺激，均可促進(jìn)線粒體膜去極化，造成線粒體腫脹，從而誘發(fā)細(xì)胞凋亡。反之，SIRT3可通過(guò)去乙酰化親環(huán)素D減少ROS累積及促進(jìn)線粒體氧化磷酸化，延遲mPTP的形成和開(kāi)放，保證線粒體基質(zhì)中與代謝和生存相關(guān)信號(hào)傳導(dǎo)的正常進(jìn)行，進(jìn)而延緩細(xì)胞凋亡，維持細(xì)胞生長(zhǎng)[20,87]。

SIRT3除了參與能量代謝平衡及抗氧化應(yīng)激作用，其在細(xì)胞內(nèi)還調(diào)控細(xì)胞周期，通過(guò)抑制抑癌基因活性、保護(hù)線粒體完整性及控制Ca2+水平，從而抑制細(xì)胞凋亡，保護(hù)細(xì)胞活性，延長(zhǎng)細(xì)胞壽命。

綜上所述，SIRT3在功能方面主要表現(xiàn)為能量代謝平衡、抗氧化應(yīng)激及調(diào)控細(xì)胞周期。在SIRT3參與的整個(gè)生命過(guò)程中，不難發(fā)現(xiàn)其與應(yīng)激狀態(tài)下細(xì)胞自身恢復(fù)內(nèi)穩(wěn)態(tài)有著密切相關(guān)性?？梢哉J(rèn)為，SIRT3是機(jī)體在進(jìn)化過(guò)程中衍生出來(lái)適應(yīng)外界快速變化的調(diào)控模式，其通過(guò)多個(gè)層面(能量代謝、氧化應(yīng)激、細(xì)胞信號(hào)通路等)發(fā)揮作用，從而維持正常生命活動(dòng)。

3 SIRT3與心血管疾病

SIRT3在細(xì)胞代謝、生長(zhǎng)、凋亡和生長(zhǎng)中具有重要的調(diào)控作用，已成為多種疾病(如2型糖尿病、神經(jīng)退行性變、炎癥和癌癥等)的治療靶點(diǎn)，具有非常重要的科學(xué)研究?jī)r(jià)值和臨床應(yīng)用前景[88]。

近年來(lái)，越來(lái)越多的研究開(kāi)始關(guān)注SIRT3與心血管疾病的關(guān)系。Wu等[89]在研究動(dòng)脈粥樣硬化發(fā)病機(jī)制時(shí)發(fā)現(xiàn)，在生理狀態(tài)下SIRT3在血管平滑肌中表達(dá)穩(wěn)定；但在高血壓及交感神經(jīng)興奮等情況下，隨著血管緊張素Ⅱ(Angiotensin II, Ang II)水平升高，血管平滑肌細(xì)胞中SIRT3表達(dá)增加，進(jìn)而抑制血管平滑肌細(xì)胞增殖。而敲除基因后，平滑肌細(xì)胞增殖明顯加快，誘發(fā)動(dòng)脈粥樣硬化的發(fā)生發(fā)展。但是，該過(guò)程的具體作用機(jī)制尚不明確。Winnik等[90]研究發(fā)現(xiàn)，敲除SIRT3并沒(méi)有影響動(dòng)脈粥樣硬化病變進(jìn)展及斑塊穩(wěn)定性。因此，SIRT3在動(dòng)脈粥樣硬化中的作用還有待于進(jìn)一步的深入研究。

一項(xiàng)間隔有氧訓(xùn)練的實(shí)驗(yàn)表明，相比于對(duì)照組，急性心肌損傷(如心肌梗死)組大鼠心肌細(xì)胞中SIRT3表達(dá)較低，而間隔有氧呼吸可上調(diào)心肌細(xì)胞中SIRT3基因的表達(dá)，進(jìn)而改善心肌受損情況[8,91]。當(dāng)心肌細(xì)胞發(fā)生缺血再灌注損傷時(shí)，SIRT3缺失加劇心肌損傷，其可能機(jī)制是：SIRT3缺失后導(dǎo)致其底物如MnSOD等不能被正常去乙酰化，心肌細(xì)胞抗氧化活性減弱，不能拮抗缺血所致的ROS累積，從而加劇缺血性心肌能量不足及與再灌注相關(guān)的氧化應(yīng)激、凋亡、炎癥及微循環(huán)應(yīng)激等反應(yīng)[92,93]。

最近，Michael等正在開(kāi)展一項(xiàng)正常飲食和間斷快速飲食(Intermittent fasting diet)與SIRT3表達(dá)的臨床觀察研究。該研究將觀察控制飲食3周，通過(guò)比較兩組受試者外周血單個(gè)核細(xì)胞中基因表達(dá)水平的差異，探討SIRT3與心血管疾病的相關(guān)性及其潛在的調(diào)控機(jī)制(網(wǎng)絡(luò)資料來(lái)源：http://clinicaltrials. gov/ct2/show/NCT02122575?term=SIRT3&rank=4.)。

而在一項(xiàng)臨床Ⅳ期研究中，將SIRT3作為一個(gè)重要的心血管疾病調(diào)控因素，以評(píng)估Omega-3和維生素E調(diào)節(jié)抗氧化酶活性的作用。研究者通過(guò)檢測(cè)基因的表達(dá)水平探討其對(duì)冠狀動(dòng)脈粥樣硬化性心臟病產(chǎn)生的影響(網(wǎng)絡(luò)資料來(lái)源：http://clinicaltrials. gov/ct2/show/NCT02011906?term=SIRT3&rank=1)。

由于SIRT3在細(xì)胞能量代謝、細(xì)胞生長(zhǎng)及凋亡等生理活動(dòng)中發(fā)揮著極為重要的調(diào)控作用，SIRT3與心血管疾病，如冠狀動(dòng)脈粥樣硬化、心肌肥厚和心肌梗死等疾病也密切相關(guān)，可能成為一種新的心血管疾病藥物治療靶點(diǎn)[4]。目前，SIRT3在心血管疾病中的作用越來(lái)越受到人們的關(guān)注，其在心血管疾病中的作用機(jī)制也亟待進(jìn)一步的研究。

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(責(zé)任編委: 張博)

The relationship of SIRT3 with cellular metabolism and cardiovascular diseases

Lijuan Cao, Xinhe Liu, Qing Zha, Qian Song, Ke Yang, Yan Liu

Protein deacetylases play an extremely crucial role in cellular biological processes and have been categorized into four families (HDACⅠ, HDACⅡ, HDACⅢ and HDACⅣ) in human. Of them, HDACⅢ, also known as the Sir2 (Silent information regulator 2) family, contains seven members, SIRT1-7, each exhibiting different cellular localization and biological function. As a major mitochondrial deacetylase, SIRT3 not only modulates cellular metabolism, but also plays important roles in apoptosis, tumor growth, aging and a number of other diseases. In this review, we summarize recent findings related to SIRT3 with an emphasis on its biological functions in regulating cell metabolism and its possible roles in cardiovascular diseases.

SIRT3; HDAC; cell metabolism; cardiovascular diseases

2014-08-26;

2014-10-10

國(guó)家自然科學(xué)基金項(xiàng)目(編號(hào)：81200204，81470547)資助

曹麗娟，碩士研究生，專業(yè)方向：動(dòng)脈粥樣硬化。Tel：021-64370045；E-mail：caolijuanqq@163.com

劉艷，博士，主任醫(yī)師，碩士生導(dǎo)師，研究方向：動(dòng)脈粥樣硬化。E-mail：liuyan_ivy@126.com

10.16288/j.yczz.14-283

網(wǎng)絡(luò)出版時(shí)間: 2014-9-24 14:14:22

URL: http://www.cnki.net/kcms/detail/11.1913.R.20140926.1342.005.html