張文，楊巍

1 心肌缺血/再灌注損傷

對(duì)于急性ST段抬高型心肌梗死（STEMI）患者，采用經(jīng)皮冠狀動(dòng)脈介入治療（PCI）開通罪犯血管及時(shí)恢復(fù)血流灌注，能降低梗死面積、保護(hù)心室功能，但在1年內(nèi)仍有7%的死亡率和22%的心力衰竭（心衰）發(fā)生率，當(dāng)高風(fēng)險(xiǎn)的STEMI發(fā)生心源性休克時(shí)，1年內(nèi)的死亡率會(huì)更高，可達(dá)12%[1,2]。雖然心肌再灌注是挽救瀕死心肌的有效方法，但是，在此過程的早期階段又造成了心肌的額外損傷，比如擾亂離子穩(wěn)態(tài)、活性氧的過量產(chǎn)生、激活炎癥反應(yīng)、引起線粒體功能紊亂和鈣超載等，從而降低了心肌再灌注的獲益，這一現(xiàn)象稱為——心肌缺血/再灌注（I/R）損傷[3-6]。大多數(shù)學(xué)者認(rèn)為即使單純的PCI恢復(fù)心肌灌注后可以降低心肌梗死面積，但再灌注損傷仍可占總梗死面積的50%[5]。而且，隨著科技的發(fā)展，雖然新型抗血小板、抗凝藥物的應(yīng)用改善再灌注血流，但對(duì)于PCI術(shù)后的患者再灌注損傷無(wú)明顯作用。對(duì)于患者，其心肌梗死面積與心肌左室重塑、心衰及PCI術(shù)后的預(yù)后緊密聯(lián)系。Larose 等表示當(dāng)心肌梗死面積≥左室面積的23%時(shí)，易發(fā)生心衰等惡性心血管事件[7]。如何降低心肌I/R損傷并改善預(yù)后成為研究熱點(diǎn)。通過大量的動(dòng)物試驗(yàn)，發(fā)現(xiàn)了許多具有預(yù)防心肌再灌注損傷的措施，如抗氧化劑、鎂劑、鈣通道抑制劑、抗炎藥物、阿托伐他汀、極化液、腺苷等，但這些方法從實(shí)驗(yàn)轉(zhuǎn)化到臨床應(yīng)用并獲利于患者卻非常困難。

2 缺血后適應(yīng)及其臨床應(yīng)用

有研究首次報(bào)道在再灌注開始時(shí)迅速進(jìn)行幾個(gè)短暫的缺血與再灌注的循環(huán)可以降低狗的心肌梗死面積[8]。之后這項(xiàng)發(fā)現(xiàn)迅速被用于多種實(shí)驗(yàn)?zāi)Ｐ?，發(fā)現(xiàn)通過短時(shí)間的心肌缺血打斷再灌注過程來調(diào)節(jié)心肌缺血環(huán)境，增加心肌對(duì)缺血/再灌注損傷的耐受能力，可顯著地保護(hù)心肌細(xì)胞避免缺血/再灌注損傷，該現(xiàn)象稱為缺血后適應(yīng)（IPostC）[9,10]。Staat等將這種方法迅速用于臨床，并表明缺血后適應(yīng)，即在罪犯血管用四個(gè)1 min缺血和1 min灌注的循環(huán)，在STEMI患者PCI術(shù)后可以使心肌梗死面積降低36%[11]。另外，有研究表明在冠狀動(dòng)脈完全閉塞（TIMI 0級(jí)）的STEMI患者中，IPostC處理后患者獲益最大[12]，但是其保護(hù)機(jī)制尚不清楚，考慮到臨床手術(shù)的可操作性及臨床效果的顯著性，對(duì)IPostC減輕I/R損傷的機(jī)制還需進(jìn)一步研究。

3 缺血后適應(yīng)對(duì)心肌缺血/再灌注損傷的作用及其機(jī)制

3.1 IPostC通過促進(jìn)自噬降低心肌I/R損傷 自噬是吞噬自體胞漿內(nèi)老化或損傷的蛋白及細(xì)胞器并使其包被進(jìn)入囊泡，與溶酶體融合形成自噬溶酶體，降解其所包裹內(nèi)容物的過程，從而完成細(xì)胞自體的新陳代謝和一些細(xì)胞器的更新[13]。一些研究表明自噬在心肌I/R損傷中發(fā)揮重要作用。當(dāng)在可調(diào)控的范圍內(nèi)促進(jìn)自噬可以在I/R損傷中補(bǔ)償線粒體損傷和建立蛋白質(zhì)穩(wěn)態(tài)[14]。Hao等通過動(dòng)物模型發(fā)現(xiàn)，IPostC和I/R組相比較，心肌梗死面積降低，心肌結(jié)構(gòu)紊亂、細(xì)胞間質(zhì)水腫等減輕，保留了心肌的正常結(jié)構(gòu)，而且線粒體碎片的量及體積的減小程度都顯著改善，而當(dāng)給予I/R心肌IPostC加上自噬抑制劑處理時(shí)，IPostC的這種心肌保護(hù)作用就消失了，出現(xiàn)心肌細(xì)胞壞死、細(xì)胞核溶解和顯著的心肌結(jié)構(gòu)紊亂[15]。由此可見自噬可以被IPostC所調(diào)控，并且參與了IPostC的心肌保護(hù)機(jī)制。另外，還有報(bào)道稱IPostC可以通過促進(jìn)自噬減輕氧化應(yīng)激從而抑制再灌注損傷[16]，其具體機(jī)制還需進(jìn)一步研究。

3.2 IPostC通過調(diào)節(jié)神經(jīng)元型一氧化氮合酶途徑降低心肌I/R損傷 心肌I/R損傷機(jī)制中氧化應(yīng)激和鈣超載是主要途徑[2]，主要通過產(chǎn)生過量?jī)?nèi)源性的活性氧和氮氧化物發(fā)揮作用[17]。雖然一氧化氮（NO）在再灌注心肌保護(hù)的方法如缺血預(yù)適應(yīng)和IPostC中都發(fā)揮著重要作用，但實(shí)際上NO在心肌I/R損傷中是一把雙刃劍[18]。NO在經(jīng)典的環(huán)磷酸鳥苷環(huán)化酶（cGMP）介導(dǎo)的信號(hào)通路中發(fā)揮作用，但最近的研究表明NO調(diào)節(jié)的心肌功能也受到氮氧化物酶系統(tǒng)的限制[19]。內(nèi)皮型一氧化氮合酶（eNOS）位于細(xì)胞膜小凹，調(diào)節(jié)細(xì)胞膜L型鈣通道，神經(jīng)元型一氧化氮合酶（nNOS）位于肌漿網(wǎng)和線粒體中，通過維持鈣循環(huán)和亞硝基——氧化還原反應(yīng)來調(diào)節(jié)肌漿網(wǎng)和線粒體的功能[20-22]。有報(bào)道稱nNOS大量表達(dá)可以保護(hù)小鼠心肌避免I/R損傷，但是，同時(shí)也增加了小鼠室性心律失常和心肌梗死后的死亡率[23]。Hu等在離體小鼠心臟中發(fā)現(xiàn)，IPostC組與I/R組相較而言，IPostC顯著促進(jìn)了左室收縮力的恢復(fù)，降低了左室舒張末壓水平和血漿中乳酸脫氫酶（LDH）水平，而nNOS抑制劑卻能消除IPostC的心肌保護(hù)能力[24]，提示IPostC通過調(diào)節(jié)nNOS途徑發(fā)揮心肌保護(hù)作用。

3.3 IPostC通過下調(diào)鈣敏感受體降低心肌I/R損傷 鈣敏感受體（CaSR）調(diào)節(jié)機(jī)體多個(gè)組織和器官的鈣代謝平衡[25]。在2003年首次報(bào)道了CaSR存在于小鼠心肌組織[26]。CaSR在心肌組織中為G蛋白偶聯(lián)受體，可以通過激活磷脂酶C（PLC）促進(jìn)3-磷酸磷脂酰肌醇（IP3）的產(chǎn)生，進(jìn)而促進(jìn)肌漿網(wǎng)中鈣離子釋放入線粒體內(nèi)，通過啟動(dòng)線粒體和肌漿網(wǎng)的凋亡通路誘發(fā)心肌凋亡[27]。曾有報(bào)道稱在心肌I/R損傷過程中，CaSR過度表達(dá)，引起鈣超載促進(jìn)心肌細(xì)胞凋亡，而IPostC可以下調(diào)CaSR的表達(dá)起到心肌保護(hù)作用[28,29]。隨后實(shí)驗(yàn)中發(fā)現(xiàn)，IPostC通過下調(diào)CaSR通路的心肌保護(hù)作用離不開ATP敏感性鉀通道（K+-ATP），是多種心肌保護(hù)方法如缺血預(yù)適應(yīng)、遠(yuǎn)程預(yù)處理等過程中最后的效應(yīng)受體，而K+-ATP通道的開放則是CaSR下調(diào)后的下游效應(yīng)[29,30]。在心肌I/R損傷過程中的缺血階段，機(jī)體通過上調(diào)CaSR而誘發(fā)鈣超載，在再灌注階段這種游離鈣的釋放被無(wú)限制放大，造成心肌損傷；而IPostC可通過下調(diào)CaSR，使K+-ATP通道開放，維持心肌細(xì)胞內(nèi)的ATP代謝平衡[31]，并抑制線粒體膜滲透轉(zhuǎn)換孔的開放，保持線粒體功能穩(wěn)定[32]。這些結(jié)果都表明CaSR是I/R損傷階段誘發(fā)鈣超載的重要靶點(diǎn)，而調(diào)控CaSR可能是降低I/R損傷的一個(gè)潛在方法。

4 現(xiàn)狀與展望

缺血性心肌病發(fā)病率和死亡率較高，及時(shí)恢復(fù)阻塞血管血流，是降低STEMI患者死亡率有效方法，但隨之產(chǎn)生的心肌I/R損傷及預(yù)后都是不可忽視的問題。近年來，經(jīng)過不斷探索及大量實(shí)驗(yàn)研究，普遍認(rèn)為缺血后適應(yīng)可以通過改變心肌缺血環(huán)境，增加心肌耐受能力，從而降低心肌I/R損傷，但由于目前報(bào)道的相關(guān)實(shí)驗(yàn)都是動(dòng)物實(shí)驗(yàn)及小型的臨床實(shí)驗(yàn)，其具體機(jī)制尚未闡明，在臨床上缺血后適應(yīng)未得到廣泛推廣，因此還需進(jìn)一步大量多中心研究探究。

參 考 文 獻(xiàn)

[1]Bulluck H,Yellon DM,Hausenloy DJ. Reducing myocardial infarct size:challenges and future opportunities[J]. Heart,2016,102(5):341-8.

[2]Hausenloy DJ,Botker HE,Engstrom T,et al. Targeting reperfusion injury in patients with ST-segment elevation myocardial infarction: trials and tribulations[J]. Eur Heart J,2017,38(13):935-41.

[3]Hausenloy DJ,Yellon MD. Targeting myocardial reperfusion injury--the search continues[J]. N Engl J Med,2015,373(11):1073-5.

[4]Granger DN,Kvietys PR. Reperfusion injury and reactive oxygen species: The evolution of a concept[J]. Redox Biology,2015,6:524-51.

[5]Hausenloy DJ,Yellon MD. Myocardial ischemia-reperfusion injury: a neglected therapeutic target[J]. J Clin Invest,2013,123(1):92-100.

[6]Jing G,Shou-Bao W,Tian-Yi Y,et al. Coptisine protects rat heart against myocardial ischemia/reperfusion injury by suppressing myocardial apoptosis and inflammation[J]. Atherosclerosis,2013,231(2):384-91.

[7]Larose E,Rodes-Cabau J,Pibarot P,et al. Predicting late myocardial recovery and outcomes in the early hours of ST-segment elevation myocardial infarction traditional measures compared with microvascular obstruction, salvaged myocardium, and necrosis characteristics by cardiovascular magnetic resonance[J]. J Am Coll Cardiol,2010,55(22):2459-69.

[8]Zhao ZQ,Corvera JS,Halkos ME,et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning[J]. Am J Physiol Heart Circ Physiol,2003,285(2):H579-88.

[9]Zhao ZQ,Morris CD,Budde JM,et al. Inhibition of myocardial apoptosis reduces infarct size and improves regional contractile dysfunction during reperfusion[J]. Cardiovasc Res,2003,59(1):132-42.

[10]Maslov LN,Podoksenov AY,Khaliulin IG. Ischaemic postconditioning of the heart. Analysis of experimental findings[J]. Angiol Sosud Khir,2016,22(4):8-16.

[11]Thibault H,Angoulvant D,Bergerot C,et al. Postconditioning the human heart[J]. Heart Metab,2007,37(37):19-22.

[12]Sorensson P,Saleh N,Bouvier F,et al. Effect of postconditioning on infarct size in patients with ST elevation myocardial infarction[J].Heart,2010,96(21):1710-5.

[13]Loos B,Engelbrecht AM,Lockshin RA,et al. The variability of autophagy and cell death susceptibility: Unanswered questions[J]. Autophagy,2013,9(9):1270-85.

[14]Quinsay MN,Thomas RL,Lee Y,et al. Bnip3-mediated mitochondrial autophagy is independent of the mitochondrial permeability transition pore[J]. Autophagy,2010,6(7):855.

[15]Hao M,Zhu S,Hu L,et al. Myocardial Ischemic Postconditioning Promotes Autophagy against Ischemia Reperfusion Injury via the Activation of the nNOS/AMPK/mTOR Pathway[J]. Int J Mol Sci,2017,18(3):E614.

[16]Zhang YL,Yao YT,Fang NX,et al. Restoration of autophagic flux in myocardial tissues is required for cardioprotection of sevoflurane postconditioning in rats[J]. Acta Pharmacol Sin,2014,35(6):758-69.

[17]Okada H,Lai NC,Kawaraguchi Y,et al. Integrins protect cardiomyocytes from ischemia/reperfusion injury[J]. J Clin Invest,2013,123(10):4294-308.

[18]Belge C,Massion PB,Pelat M,et al. Nitric oxide and the heart: update on new paradigms[J]. Ann NY Acad Sci,2005,1047(1):173-82.

[19]Sun J,Picht E,Ginsburg KS,et al. Hypercontractile female hearts exhibit increased S-nitrosylation of the L-type Ca2+ channel α1 subunit and reduced ischemia/reperfusion injury[J]. Circ Res,2006,98(3):403-11.

[20]Xu KY,Huso DL,Dawson TM,et al. Nitric oxide synthase in cardiac sarcoplasmic reticulum[J]. P Natl Acad Sci USA,1999,96(2):657-62.

[21]Zhang YH. Nitric oxide signalling and neuronal nitric oxide synthase in the heart under stress[J]. F1000Res,2017,6:742.

[22]Kanai AJ,Pearce LL,Clemens PR,et al. Identification of a neuronal nitric oxide synthase in isolated cardiac mitochondria using electrochemical detection[J]. Proc Natl Acad Sci USA,2001,98(24):14126-31.

[23]Burger DE,Lu X,Lei M,et al. Neuronal nitric oxide synthase protects against myocardial infarction-induced ventricular arrhythmia and mortality in mice[J]. Circulation,2009,120(14): 1345-54.

[24]Hu L,Wang J,Zhu H,et al. Ischemic postconditioning protects the heart against ischemia-reperfusion injury via neuronal nitric oxide synthase in the sarcoplasmic reticulum and mitochondria[J]. Cell Death &Disease,2016,7(5):e2222.

[25]Hu F,Pan L,Zhang K,et al. Elevation of Extracellular Ca2+ Induces Store-Operated Calcium Entry via Calcium-Sensing Receptors:A Pathway Contributes to the Proliferation of Osteoblasts[J]. Plos One,2014,9(9):e107217.

[26]Wang R,Xu C,Zhao W,et al. Calcium and polyamine regulated calciumsensing receptors in cardiac tissues[J]. Eur J Biochem,2003,270(12):2680-8.

[27]Lu FH,Fu SB,Leng X,et al. Role of the calcium-sensing receptor in cardiomyocyte apoptosis via the sarcoplasmic reticulum and mitochondrial death pathway in cardiac hypertrophy and heart failure[J]. Cell Physiol Biochem,2013,31(4-5):728-74.

[28]Onukwufor JO,Stevens D,Kamunde C. Bioenergetic and volume regulatory effects of mitoKATP channel modulators protect against hypoxia-reoxygenation-induced mitochondrial dysfunction[J]. J Exp Biol,2016,219(Pt 17):2743-51.

[29]Cao S,Liu Y,Sun W,et al. Genome-wide expression profiling of anoxia/reoxygenation in rat cardiomyocytes uncovers the role of MitoKATP in energy homeostasis[J]. Oxid Med Cell Long,2015,20(75):65-76.

[30]Gan R,Hu G,Zhao Y,et al. Post-conditioning protecting rat cardiomyocytes from apoptosis via attenuating calciumsensing receptor-induced endo (sarco) plasmic reticulum stress[J]. Mole Cell Biochem,2012,361(1-2):123-34.

[31]Zhang L,Cao S,Deng S,et al. Ischemic postconditioning and pinacidil suppress calcium overload in anoxiareoxygenation cardiomyocytes via downregulation of the calcium-sensing receptor[J]. Peer J,2016,4:e2612.

[32]Valls-Lacalle L,Barba I,Miro-Casas E,et al. Succinate dehydrogenase inhibition with malonate during reperfusion reduces infarct size by preventing mitochondrial permeability transition[J]. Cardiovasc Res,2016,109(3):374-84.