曹麗娟，劉昕訸，查晴，宋倩，楊克，劉艷

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SIRT3與細胞代謝及心血管疾病的相關性

曹麗娟，劉昕訸，查晴，宋倩，楊克，劉艷

上海交通大學醫(yī)學院附屬瑞金醫(yī)院心血管內科，上海 200025

蛋白去乙酰化酶在細胞生理過程中發(fā)揮著極為重要的作用。人蛋白去乙酰化酶包括HDACⅠ、HDACⅡ、HDACⅢ和HDACⅣ4個家族。其中第Ⅲ類即Sir2(Silent information regulator 2)家族包括7個成員——SIRT1~ SIRT7，每個成員都具有不同的細胞定位，并且發(fā)揮不同的生物學功能。作為主要定位于線粒體的組蛋白去乙酰化酶，SIRT3不僅調節(jié)細胞的能量代謝，并在細胞凋亡、腫瘤生長和一些疾病中發(fā)揮作用。文章綜述了SIRT3在細胞代謝中的生物學功能以及其在心血管疾病中的研究進展。

SIRT3；組蛋白去乙?；?；細胞代謝；心血管疾病

蛋白質乙?；?去乙?；且环N非常重要的翻譯后修飾，也是調節(jié)酶活性以適應細胞代謝和能量改變的一個重要方式。在酵母(Meyen ex Hansen)中，蛋白去乙?；阜譃镽pd3(Reduced potassium dependency 3)、Hda1(Histone deacetylase 1)和Sir2(Silent information regulator 2)共3個家族，根據(jù)對酵母種系發(fā)育中組蛋白去乙酰化酶(Histone deacetylases, HDACs)結構的同源性分析[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，主要分布于細胞核中，并在各類組織細胞中廣泛表達。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在細胞核和細胞質均有分布，主要在心臟、肺、骨骼肌中表達。Ⅱ類HDACs在細胞核、細胞質的分布受肌細胞增強因子2(Myocyte enhancer factor 2, MEF2)和14-3-3蛋白調節(jié)[3]。正常情況下，MEF2與Ⅱ類HDACs結合并以復合物的形式定位于細胞核以維持細胞的穩(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蛋白結合而滯留在細胞漿內，同時MEF2可被磷酸化并調控相應基因的表達，導致肌細胞增生[3~5]。HDAC11兼有Ⅰ類和Ⅱ類HDACs特性，單獨歸為第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是一類在進化中高度保守的蛋白質，存在于原核和真核生物中，具有NAD+蛋白活性。

Sirtuins是一類NAD+依賴性組蛋白去乙酰化酶，其去乙?；饔脽o特異性，除組蛋白底物外，還可使非組蛋白底物去乙?；痆8~10]。哺乳動物Sirtuins家族有7個成員(SIRTl~SIRT7)，其基因定位、組織表達、細胞定位、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、細胞代謝、細胞生長和凋亡以及晝夜節(jié)律等方面起重要的調節(jié)作用[11]。

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

1 SIRT3定位與分布

人基因位于11號染色體p15.5(11p15.5)，由21 902個堿基構成。基因編碼蛋白由399個氨基酸構成，分子量約44 kDa。其N端包含一個由25個氨基酸殘基組成的線粒體定位信號肽，在線粒體基質中被肽酶識別剪切后，形成一個28 kDa大小的成熟酶蛋白[50,51]。兩個可變剪接轉錄變體編碼兩種不同蛋白亞型，分別為1~399氨基酸(全長型SIRT3)和142~399氨基酸(成熟型SIRT3)。

Cooper等[52]認為，全長型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)，細胞在應激刺激后，全長型SIRT3可被酶剪切為成熟SIRT3[53,54]。由于缺乏線粒體定位信號，成熟型SIRT3非特異性地分布于線粒體或細胞質中，甚至出現(xiàn)于細胞核中。研究發(fā)現(xiàn)，無論是定位在線粒體、細胞質還是細胞核，SIRT3均具去乙?；富钚訹41]。因此，SIRT3的去乙?；δ芸赡芘c其細胞定位無關。

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。代謝活性越強的器官，如肝臟、棕色脂肪組織、心臟及腎臟等，其SIRT3表達也越高。研究表明，在低溫環(huán)境中，機體通過增強棕色脂肪細胞中的SIRT3表達，去乙酰化并激活解偶聯(lián)蛋白活性，提高機體代謝率以維持體溫[51]。同樣，運動、節(jié)食和能量限制等均可增強SIRT3表達活性；而長期高脂飲食會使其表達降低[7,17,21]。雖然SIRT3組織特異性分布的具體機制尚不清楚，但是其高表達于高能量代謝器官，提示其與細胞能量代謝調控密切相關。

2 SIRT3功能

線粒體的主要功能為能量合成，同時還具有調節(jié)活性氧(Reactive oxygen species, ROS)生成、細胞代謝(如膽固醇、激素合成等)及細胞凋亡等生物活性。SIRT3作為線粒體中主要的去乙?；福烧{節(jié)細胞能量合成和線粒體生理活性，同時參與調控細胞生存維持所需生物分子(如蛋白質及脂質等)合成等作用[17,55]。SIRT3參與幾乎所有與機體細胞代謝相關信號通路的調控，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]、蛋白質合成[7,8]及細胞生長和凋亡[20]等(圖1)。

研究表明，SIRT3表達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、衰老及運動等[17,27,62]；內部因素如NAD+/NADH活性變化、過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)的表達及激活、雌激素受體反應元件(Estrogen receptor responsive element, ERRE)的激活及羥化作用和瘦素表達水平等[8,17,35,38](圖1)。

中英文對照縮表見附表1。

環(huán)境因素(晝夜、氣溫及應激等)對機體的各項生命活動具有非常重要的影響，往往會造成機體中臟器、細胞乃至分子的波動，而這些影響往往與能量密切相關。但是，各項生命活動均需一個相對穩(wěn)定的內部環(huán)境，因此需要一系列基因參與其內維持能量網(wǎng)絡的穩(wěn)態(tài)。正是基于這樣一種生命維持模式，SIRT3的表達對于外界及細胞內多種刺激因素產(chǎn)生應答，同時，其下游調控基因也多與能量代謝密切相關。SIRT3作為能量代謝網(wǎng)絡中一個重要環(huán)節(jié)調節(jié)機體自身能量代謝平衡，從而使得機體能夠應對環(huán)境的變化。

2.1 SIRT3與能量代謝

能量代謝是細胞生存的基礎活動，當細胞能量需求或供給發(fā)生變化時，細胞代謝就會發(fā)生一系列調整以維持細胞生存。當能量供應減少(如能量限制，即在保證機體正常營養(yǎng)需求情況下，減少機體30%~40%能量攝入)或能量需求增加(如寒冷暴露)時，一方面線粒體SIRT3通過去乙?；€粒體核糖體蛋白L10，降低50%~60%線粒體核糖體內蛋白質(如細胞色素C氧化酶亞基II)合成，降低葡萄糖代謝速率及與其相關的氧化磷酸化水平[8]。

另一方面，線粒體SIRT3還通過去乙酰化作用增強長鏈?；o酶A脫氫酶、烯酰輔酶A水合酶、3-羥酰基輔酶A脫氫酶及親環(huán)素D等蛋白活性，促進細胞脂肪酸氧化；激活羥甲戊二酰輔酶A合成酶2，促進酮體生成；提高谷氨酸脫氫酶、乙酰輔酶A合成酶2、蘋果酸脫氫酶及琥珀酸脫氫酶等酶活性，加速細胞三羧酸循環(huán)；激活氨甲酰基磷酸合成酶Ⅰ和鳥氨酸氨甲?；D移酶，加速尿素循環(huán)，促進氨基酸氧化[13,14,21,24,29]。

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

由此可見，SIRT3參與調節(jié)能量代謝的各個方面，對機體能量代謝各項機能起著不可替代的調控作用，通過維持機體內能量代謝平衡，從而保護應激條件下器官生理活性。

2.2 SIRT3與ROS

氧化應激所導致的細胞內ROS累積與心肌肥厚[20,44,64,65]、冠狀動脈粥樣硬化[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(如年齡相關的聽力損傷)[9,72]、阿爾茲海默病[73,74]及腫瘤[63,75~78]等疾病密切相關。

Bell等[79]認為，線粒體SIRT3可直接去乙酰化并激活抗氧化因子錳超氧化物歧化酶(Manganese sup-eroxide dismutase, MnSOD)和異檸檬酸脫氫酶2(Isoci-trate dehydrogenase 2, IDH2)，啟動抗氧化過程，防止ROS累積；Jacobs等[56]還發(fā)現(xiàn)，細胞核內SIRT3可通過去乙酰化從而增加轉錄因子叉形頭轉錄因子的O亞型(Forkhead box O3, FOXO3a)表達，而后者則進一步促進MnSOD和IDH2表達減輕氧化應激對細胞的損傷，延緩相關疾病的發(fā)生和發(fā)展[56,79]。SIRT3通過直接和間接作用下調ROS水平，促進一氧化碳合成酶(Endothelial nitric oxide synthase, eNOS)生成，改善血管內皮功能，從而延緩動脈粥樣硬化形成和進展[80]。

但是，當細胞內SIRT3表達水平下降時，線粒體中的MnSOD和IDH2等抗氧化因子活性也會隨之下降，造成ROS累積，導致線粒體功能紊亂，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]。其導致胰島素抵抗的可能機制為：伴隨SIRT3水平降低，細胞內ROS清除作用削減，ROS在細胞內大量累積，從而激活氧化應激相關信號通路蛋白PKC (Protein kinase C)、S6激酶和JNK(Jun N-terminal kinase)等，下調胰島素受體底物-1(Insulin receptor substrate, IRS-1)酪氨酸磷酸化水平，降低PI3K及Akt磷酸化水平，抑制胰島素信號通路，誘發(fā)胰島素抵抗，從而導致與胰島素抵抗密切相關的2型糖尿病發(fā)生和發(fā)展。

SIRT3通過ROS信號通路還與腫瘤的發(fā)生發(fā)展密切相關。SIRT3表達上升可降低ROS水平，使低氧誘導因子-1α(Hypoxia inducible factor-1, HIF-1α)穩(wěn)定性下降，通過抑制ROS累積和HIF-1α活性從而抑制腫瘤細胞生長。但是，當SIRT3水平降低時，ROS累積增加，HIF-1α表達上調，穩(wěn)定性及活性增加，進而誘導缺氧反應蛋白(如血管內皮生長因子)的表達，加速糖酵解代謝，促進營養(yǎng)物質氧化和ATP產(chǎn)生[63]，增加腫瘤細胞在缺氧環(huán)境下的適應性，促進腫瘤細胞增殖、新生血管生成、侵襲和遷移[43,79]。

ROS是導致大部分疾病發(fā)生發(fā)展的重要因素，而調節(jié)ROS累積對于疾病的發(fā)生和發(fā)展具有決定性作用，SIRT3的表達水平與ROS累積具有負相關性。在氧化應激時，其表達具有應激性升高的特點，起到保護細胞對抗氧化應激的作用。但是，當應激反應進一步放大時，其表達大幅下降，原有的平衡調節(jié)作用喪失，相反促進氧化應激反應，最終加速疾病進展。調節(jié)SIRT3表達可有效對抗氧化應激從而逆轉病程。

2.3 SIRT3與細胞凋亡和生長

在細胞凋亡和生長過程中，SIRT3具有非常復雜的生物效應。一方面，SIRT3可通過調節(jié)Bcl-2或JNK2活性，促進細胞凋亡[82]；另一方面，SIRT3又可通過核轉錄因子FOXO3a和Ku70信號通路，參與維持細胞生存[53,82,83]。

Allison等[82]在研究腫瘤發(fā)病機制時發(fā)現(xiàn)，敲除Bcl-2可引發(fā)細胞凋亡，但是共敲除SIRT3后，反而延緩了細胞的凋亡進程[82,84]，提示腫瘤細胞中的SIRT3參與Bcl-2/p53凋亡信號通路。Allison等[82]研究還表明，JNK1可通過促進SIRT3轉錄，加速JNK-2/JNK1相關的非P53依賴性凋亡。

在生理狀況下，SIRT3還可通過去乙?；孜顰ceCS2參與Bcl-2/p53誘導的細胞生長停滯反應。研究發(fā)現(xiàn)，敲除Bcl-2可誘導細胞停滯在G1期，此過程依賴于SIRT3/AceCS2，推測SIRT3/AceCS2是細胞生長中不可或缺的調節(jié)因素。SIRT3可能通過該途徑延長機體壽命。因此，SIRT3可能是一個長壽因子[85]。

在慢性炎癥刺激等應激情況下，SIRT3可通過以下方式參與細胞凋亡的調控：(1)MnSOD和IDH2途徑。SIRT3去乙酰化FOXO3a，提高其底物MnSOD和IDH2活性，后兩者可減少細胞內ROS含量。線粒體SIRT3還能直接使MnSOD和IDH2蛋白去乙?；鰪娖淇寡趸钚?，減少ROS累積，從而降低ROS對細胞的損傷。(2)Ku70途徑。SIRT3去乙?；疜u70，使后者與促凋亡蛋白Bax緊密結合，阻止Bax由細胞核轉運至線粒體，從而抑制細胞凋亡[85,86]。SIRT3通過這些途徑來維持線粒體的內環(huán)境穩(wěn)定，以保護線粒體的正常生理功能，抑制細胞凋亡和壞死。

在生理情況下，大多數(shù)離子和溶質都不能通過線粒體屏障，這有利于保持細胞膜內、外兩側Ca2+離子平衡和正常的細胞膜電位以維持細胞正常生理功能。然而，隨著年齡的增長，細胞內環(huán)境的改變，如ROS和Ca2+水平升高，可誘導線粒體膜表面通透性轉換孔(Mitochondrial permeability transition pore, mPTP)的形成。在病理情況下，慢性低水平的應激刺激可誘導線粒體上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，均可促進線粒體膜去極化，造成線粒體腫脹，從而誘發(fā)細胞凋亡。反之，SIRT3可通過去乙?；H環(huán)素D減少ROS累積及促進線粒體氧化磷酸化，延遲mPTP的形成和開放，保證線粒體基質中與代謝和生存相關信號傳導的正常進行，進而延緩細胞凋亡，維持細胞生長[20,87]。

SIRT3除了參與能量代謝平衡及抗氧化應激作用，其在細胞內還調控細胞周期，通過抑制抑癌基因活性、保護線粒體完整性及控制Ca2+水平，從而抑制細胞凋亡，保護細胞活性，延長細胞壽命。

綜上所述，SIRT3在功能方面主要表現(xiàn)為能量代謝平衡、抗氧化應激及調控細胞周期。在SIRT3參與的整個生命過程中，不難發(fā)現(xiàn)其與應激狀態(tài)下細胞自身恢復內穩(wěn)態(tài)有著密切相關性?？梢哉J為，SIRT3是機體在進化過程中衍生出來適應外界快速變化的調控模式，其通過多個層面(能量代謝、氧化應激、細胞信號通路等)發(fā)揮作用，從而維持正常生命活動。

3 SIRT3與心血管疾病

SIRT3在細胞代謝、生長、凋亡和生長中具有重要的調控作用，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，具有非常重要的科學研究價值和臨床應用前景[88]。

近年來，越來越多的研究開始關注SIRT3與心血管疾病的關系。Wu等[89]在研究動脈粥樣硬化發(fā)病機制時發(fā)現(xiàn)，在生理狀態(tài)下SIRT3在血管平滑肌中表達穩(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，血管平滑肌細胞中SIRT3表達增加，進而抑制血管平滑肌細胞增殖。而敲除基因后，平滑肌細胞增殖明顯加快，誘發(fā)動脈粥樣硬化的發(fā)生發(fā)展。但是，該過程的具體作用機制尚不明確。Winnik等[90]研究發(fā)現(xiàn)，敲除SIRT3并沒有影響動脈粥樣硬化病變進展及斑塊穩(wěn)定性。因此，SIRT3在動脈粥樣硬化中的作用還有待于進一步的深入研究。

一項間隔有氧訓練的實驗表明，相比于對照組，急性心肌損傷(如心肌梗死)組大鼠心肌細胞中SIRT3表達較低，而間隔有氧呼吸可上調心肌細胞中SIRT3基因的表達，進而改善心肌受損情況[8,91]。當心肌細胞發(fā)生缺血再灌注損傷時，SIRT3缺失加劇心肌損傷，其可能機制是：SIRT3缺失后導致其底物如MnSOD等不能被正常去乙酰化，心肌細胞抗氧化活性減弱，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的氧化應激、凋亡、炎癥及微循環(huán)應激等反應[92,93]。

最近，Michael等正在開展一項正常飲食和間斷快速飲食(Intermittent fasting diet)與SIRT3表達的臨床觀察研究。該研究將觀察控制飲食3周，通過比較兩組受試者外周血單個核細胞中基因表達水平的差異，探討SIRT3與心血管疾病的相關性及其潛在的調控機制(網(wǎng)絡資料來源：http://clinicaltrials. gov/ct2/show/NCT02122575?term=SIRT3&rank=4.)。

而在一項臨床Ⅳ期研究中，將SIRT3作為一個重要的心血管疾病調控因素，以評估Omega-3和維生素E調節(jié)抗氧化酶活性的作用。研究者通過檢測基因的表達水平探討其對冠狀動脈粥樣硬化性心臟病產(chǎn)生的影響(網(wǎng)絡資料來源：http://clinicaltrials. gov/ct2/show/NCT02011906?term=SIRT3&rank=1)。

由于SIRT3在細胞能量代謝、細胞生長及凋亡等生理活動中發(fā)揮著極為重要的調控作用，SIRT3與心血管疾病，如冠狀動脈粥樣硬化、心肌肥厚和心肌梗死等疾病也密切相關，可能成為一種新的心血管疾病藥物治療靶點[4]。目前，SIRT3在心血管疾病中的作用越來越受到人們的關注，其在心血管疾病中的作用機制也亟待進一步的研究。

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(責任編委: 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

國家自然科學基金項目(編號：81200204，81470547)資助

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

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

10.16288/j.yczz.14-283

網(wǎng)絡出版時間: 2014-9-24 14:14:22

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