【關(guān)鍵詞】冠狀動脈微循環(huán)障礙;運(yùn)動康復(fù);內(nèi)皮功能障礙;線粒體自噬;血管周圍脂肪組織【中圖分類號】R331.37【文獻(xiàn)標(biāo)識碼】A DOI:10.12114/j.issn.1007-9572.2024.0286
【Abstract】Coronary microcirculation disorder refers to the clinical syndrome caused by the abnormal structure and/ orfunctionoftheprecoronaryrteriolesandarterioles,whichiscloselyrelatedtotheprognosisofcardiovasculardiseasessuch asacutecoronarysyndrome,coronaryofender vascularrevascularizationand heartfailure.Asanon-drug intervention for the preventionandtreatmentofcardiovasculardiseases,exerciserehabilitation improves endothelial functionandoxidative inflammationstimulationinpatients withcoronarymicrocirculationdisorders trough signaling molecules,restores mitochondrial autophagylevel,and induces functionalrecoveryofperivascularadiposetissue.Thisarticlereviewedtheresearch progresof exerciseehabilitationinterventionincoronarymicrocirculationdisorder,aimingtoprovidemoreideasandreferencesforexercise rehabilitation treatment of coronary microcirculation disorder.
【Key words】Coronary microcirculationdisorder;Sports rehabilitation;Endothelial dysfunction;Mitochondrial autophagy;Perivascular adipose tissue
隨著冠狀動脈造影(CAG)、核素灌注等影像技術(shù)的普及,冠狀動脈微循環(huán)障礙(coronarymicrocirculationdisorder,CMD)檢出率逐漸上升。CMD是指冠狀前小動脈和小動脈結(jié)構(gòu)和/或功能異常所致的臨床綜合征,與急性冠脈綜合征、冠狀動脈罪犯血管再通及心力衰竭等心血管疾病預(yù)后生存密切相關(guān)[1-2]。目前CMD 的發(fā)病機(jī)制尚不完全清楚,多數(shù)學(xué)者認(rèn)為與冠狀動脈微血管功能和/或結(jié)構(gòu)障礙有關(guān)。前者主要由一氧化氮(NO)不足引起的血管內(nèi)皮功能障礙引起,內(nèi)皮素等血管收縮因子引起血管平滑肌收縮導(dǎo)致微血管痙攣也有一定影響。而結(jié)構(gòu)障礙則主要與微血栓形成、微血管重構(gòu)及管腔狹窄、心肌間質(zhì)細(xì)胞腫脹壓迫、血管纖維化及心肌肥大、心室充盈引起的機(jī)械壓迫等有關(guān)[2]。在CMD的發(fā)病機(jī)制中,內(nèi)皮功能障礙、炎癥反應(yīng)、氧化應(yīng)激、血管稀疏、胰島素抵抗、線粒體自噬等多種因素參與其中[1]。循證醫(yī)學(xué)數(shù)據(jù)表明,以“運(yùn)動”為核心的心臟康復(fù)治療通過改善CMD患者生活方式、提高生活質(zhì)量,可降低再入院率和死亡率[2-3]。運(yùn)動康復(fù)是指通過傳統(tǒng)和現(xiàn)代的運(yùn)動方式促進(jìn)組織修復(fù),恢復(fù)運(yùn)動能力的多學(xué)科交叉模式,包括有氧運(yùn)動、抗阻運(yùn)動、聯(lián)合運(yùn)動等。既往研究認(rèn)為,降低成年人全因死亡率的益處閾值與身體活動呈劑量依賴關(guān)系[4],但也有學(xué)者指出長期參加劇烈耐力運(yùn)動可能與心房顫動、心臟重構(gòu)和冠狀動脈硬化等心血管不良事件風(fēng)險(xiǎn)增加相關(guān)[5]。由此,WHO 建議所有成年人每周應(yīng)進(jìn)行至少 150~300min 的中等強(qiáng)度有氧運(yùn)動,或75\~150 min 的高強(qiáng)度有氧運(yùn)動[6]
研究表明,對于CMD患者,除藥物治療如 β 受體阻滯劑、血管緊張素轉(zhuǎn)換酶抑制劑(ACEI)、雷諾嗪、雌激素替代療法以及丹參黃芪等中藥治療外,運(yùn)動康復(fù)是其治療的重要手段[3]。適當(dāng)強(qiáng)度的運(yùn)動訓(xùn)練可以減少活性氧和炎癥因子產(chǎn)生,減輕心肌纖維化和細(xì)胞凋亡,改善內(nèi)皮功能和線粒體自噬水平,調(diào)控心血管危險(xiǎn)因素,從而改善CMD[7]。本文就運(yùn)動康復(fù)治療CMD及其相關(guān)機(jī)制進(jìn)行綜述如下。
1 文獻(xiàn)檢索策略
以“Coronary microcirculation disorder”“Sportsrehabilitation”“Mitochondrial autophagy”“Perivascularadipose tissue”“inflammation”“Oxidative stress”為英文檢索詞,檢索PubMed、WebofScience數(shù)據(jù)庫;以“冠狀動脈微血管疾病”“運(yùn)動訓(xùn)練”“線粒體自噬”為中文檢索詞,檢索中國知網(wǎng)、萬方數(shù)據(jù)知識服務(wù)平臺,檢索時(shí)間為2012年1月—2024年7月。納入標(biāo)準(zhǔn):文獻(xiàn)內(nèi)容涉及CMD發(fā)病機(jī)制與運(yùn)動訓(xùn)練改善心血管疾病相關(guān)機(jī)制。排除標(biāo)準(zhǔn):可信度低及質(zhì)量不佳的文獻(xiàn)。最終納入文獻(xiàn)61篇。
2運(yùn)動康復(fù)改善內(nèi)皮功能障礙
內(nèi)皮功能障礙是冠狀動脈微循環(huán)障礙的主要發(fā)病機(jī)制[2],與較差的臨床預(yù)后相關(guān),主要是由于血管收縮舒張功能失衡引起,表現(xiàn)為血管擴(kuò)張劑[如NO、硫化氫( H2S )]的生物利用度降低和/或內(nèi)皮源性收縮因子[如內(nèi)皮素1(ET-1)]的增加導(dǎo)致內(nèi)皮依賴性血管舒張損害。NO的表達(dá)水平與內(nèi)皮功能密切相關(guān),病理性剪切應(yīng)力和低水平內(nèi)皮祖細(xì)胞(endothelialprogenitorcells,EPCs)動員通過影響NO的產(chǎn)生而介導(dǎo)微血管內(nèi)皮功能障礙。
2.1 運(yùn)動與NO
運(yùn)動通過上調(diào)NO水平改善微血管內(nèi)皮功能。研究發(fā)現(xiàn),8周有氧運(yùn)動促進(jìn)Apelin、Adropin蛋白釋放,抑制促內(nèi)皮型一氧化氮合酶(eNOS)解偶聯(lián)的非對稱性二甲基精氨酸(ADMA)表達(dá),而后激活磷脂肌醇3-激酶(PI3K)/蛋白激酶B(Akt)/細(xì)胞外信號調(diào)節(jié)激酶(ERK1/2)、腺苷酸活化蛋白激酶(AMPK)、血管內(nèi)皮生長因子(VEGF)受體2/ERK信號通路途徑調(diào)節(jié)NO 的表達(dá)[8]。常規(guī)運(yùn)動通過增加eNOS、線粒體解偶聯(lián)蛋白2(UCP2)和脂聯(lián)素水平上調(diào)NO的產(chǎn)生,降低硫氧還蛋白相互作用蛋白(TXNIP)/NOD樣受體熱蛋白結(jié)構(gòu)域相關(guān)蛋白3(NLRP3)炎癥小體信號級聯(lián)反應(yīng)[9]。且定期有氧運(yùn)動訓(xùn)練可顯著降低內(nèi)皮素A型(ETA)受體介導(dǎo)的 ET-1血管收縮張力[10] C
體育活動刺激骨骼肌細(xì)胞分泌釋放具有潛在心臟有益的肌因子,例如鳶尾素、腦源性神經(jīng)營養(yǎng)因子(BDNF)骨蛋白、 β 氨基異丁酸(BAIBA)等。其中鳶尾素是一種主要由骨骼肌分泌的運(yùn)動誘導(dǎo)多肽,BOSTROM等[11]發(fā)現(xiàn)運(yùn)動通過刺激過氧化物酶體增殖物激活受體 γ 輔激活因子 1α ( PGC-1α )上調(diào)Ⅲ型纖連蛋白結(jié)構(gòu)域包含蛋白5(FNDC5)表達(dá),并在血液中被蛋白酶剪切成鳶尾素。高水平鳶尾素可增加心肌微血管內(nèi)皮細(xì)胞NO表達(dá),抑制活性氧(ROS)/NLRP3通路減少促炎因子和ROS 的產(chǎn)生,延緩EPCs衰老,改善內(nèi)皮功能障礙[12]。最近的研究發(fā)現(xiàn)鳶尾素與 H2S 通過介導(dǎo)共同途徑PGC-1α/信號調(diào)節(jié)因子1(SIRT1)通路增強(qiáng)心臟保護(hù)作用[13]。
2.2 運(yùn)動與剪切應(yīng)力
在運(yùn)動訓(xùn)練期間引起的血流動力學(xué)改變增加血流剪切應(yīng)力,導(dǎo)致內(nèi)皮細(xì)胞管腔上的糖萼結(jié)構(gòu)舒展,激活鈣通道,誘導(dǎo)平滑肌松弛,調(diào)控內(nèi)皮基因表達(dá),改善心血管病患者的微血管功能[14]。低強(qiáng)度、振蕩剪切應(yīng)力通過下調(diào)內(nèi)皮保護(hù)性轉(zhuǎn)錄因子[Kruppel樣因子2和4(KLF2、4)、核因子E2相關(guān)因子2(Nrf2)]表達(dá),上調(diào)炎癥相關(guān)轉(zhuǎn)錄因子[核轉(zhuǎn)錄因子 κB (NF- κB )、激活蛋白1(AP-1)、低氧誘導(dǎo)因子 1α ( )]、黏附趨化因子[細(xì)胞間黏附因子1(ICAM-1)、血管細(xì)胞黏附因子1(VCAM-1)、單核細(xì)胞趨化蛋白1(MCP-1)]、細(xì)胞焦亡相關(guān)蛋白(Caspase-1)和促血管生長血管重塑因子[VEGF、血小板衍生生長因子(PDGF)、基質(zhì)金屬蛋白酶(MMPs)、轉(zhuǎn)化生長因子1和3(TGF-β1、3)]的表達(dá),刺激氧化酶解偶聯(lián)產(chǎn)生過多的ROS,提高內(nèi)質(zhì)網(wǎng)應(yīng)激[15]等介導(dǎo)下游效應(yīng)如血管通透性增加和微血管重構(gòu)等,也可通過Fas途徑介導(dǎo)血管平滑肌細(xì)胞凋亡。最近一項(xiàng)研究發(fā)現(xiàn),病理性機(jī)械應(yīng)力會擾亂線粒體穩(wěn)態(tài)、引發(fā)線粒體功能障礙[16]另一方面,層流剪切應(yīng)力除了上調(diào)內(nèi)皮保護(hù)因子分泌外,還通過調(diào)節(jié)miRNA-29b-3p/CX3CL1軸、Hippo/
YAP通路來減少細(xì)胞凋亡及平滑肌細(xì)胞遷移[17],以及調(diào)控線粒體生物發(fā)生等。運(yùn)動訓(xùn)練可通過增加血流層流剪切應(yīng)力調(diào)控內(nèi)皮功能的恢復(fù)。如MA等[18]發(fā)現(xiàn)運(yùn)動以過氧化物酶體增值物活化受體 γ ( PPARγ )依賴的方式在層流剪切應(yīng)力下增加內(nèi)皮中含F(xiàn)UN14域蛋白1(FUNDC1)的表達(dá),延緩因年齡帶來的冠狀動脈內(nèi)皮細(xì)胞衰老。此外,有氧運(yùn)動誘導(dǎo)剪切應(yīng)力產(chǎn)生對內(nèi)皮細(xì)胞的保護(hù)作用與上調(diào)Apelin、Adropin和下調(diào)ADMA水平有關(guān)[8]。未來維持血管生理性機(jī)械應(yīng)力或許是治療CMD的重要潛在靶點(diǎn)。
2.3 運(yùn)動與EPCs
冠狀動脈微血管保持完整性的機(jī)制涉及內(nèi)皮細(xì)胞的修復(fù)和替換過程,EPCs在微血管內(nèi)皮細(xì)胞的維持中起著重要的作用[19]。在此過程中,早期EPCs不一定會分化為成熟內(nèi)皮細(xì)胞(CECs)融入脈管系統(tǒng),但其可能會短暫地停留在受損區(qū)域,旁分泌多種調(diào)節(jié)因子如粒細(xì)胞集落刺激因子(G-CSF)、MMP-9、VEGF、PDGF、TGF- β 等[20]介導(dǎo)PDGF-BB/PDGFR- β 軸、MRTFs-SRF-CArG軸等途徑,抑制血小板聚集和血管平滑肌細(xì)胞表型轉(zhuǎn)換,誘導(dǎo)心淋巴管密度增加,刺激新生血管形成。在慢性缺血缺氧狀態(tài)下,運(yùn)動訓(xùn)練上調(diào)EPCs動員,使VEGF濃度顯著增高,促進(jìn)血管損傷后再修復(fù)。運(yùn)動通過剪切應(yīng)力介導(dǎo)煙酰胺腺嘌呤二核苷酸磷酸氧化酶(NOXs)/ROS軸、VEGF/RAS軸、 Wnt/ Notch軸、microRNA、PI3K/Akt/GSK3β等各種信號通路提高EPCs從骨髓動員到循環(huán)血液中分化為CECs,促進(jìn)受損血管修復(fù)和再內(nèi)皮化,調(diào)控血管新生,抑制新生內(nèi)膜增生阻止血管變窄,抑制血管壁的炎性反應(yīng),從而改善冠狀動脈微血管功能障礙。一項(xiàng)系統(tǒng)綜述發(fā)現(xiàn)5min 高強(qiáng)度( 100%VO2max )的有氧運(yùn)動足以增加EPCs數(shù)量,而低于運(yùn)動臨界下限或大強(qiáng)度、長時(shí)間運(yùn)動的運(yùn)動量可能會抑制EPCs動員的生理過程[21]。心血管疾病患者和健康個(gè)體進(jìn)行持續(xù)的有氧運(yùn)動(3\~5次/周,40~60min/ 次, 65%~75%VO2max )似乎更能促進(jìn)EPCs動員。有氧運(yùn)動通過減少瘦素水平并上調(diào)靜止?fàn)顟B(tài)的造血干細(xì)胞生態(tài)位因子來減少炎性白細(xì)胞的造血輸出[22]。研究發(fā)現(xiàn),運(yùn)動還通過誘導(dǎo)環(huán)氧二十碳三烯酸(EET)產(chǎn)生,促進(jìn)EPCs的血管生成功能和調(diào)節(jié)血管張力,進(jìn)而在心臟保護(hù)中起作用[23]。對心血管疾病患者靜脈給藥EPCs亦可改善其運(yùn)動能力和左心室功能,EPCs捕獲支架(表面有EPCs抗體的不銹鋼支架)是冠狀動脈支架另一個(gè)潛在應(yīng)用[24]
3運(yùn)動康復(fù)改善氧化應(yīng)激和炎癥刺激
慢性心肌缺血缺氧增強(qiáng)機(jī)體氧化應(yīng)激,導(dǎo)致過量ROS堆積,誘導(dǎo)細(xì)胞凋亡,刺激炎癥介質(zhì)釋放和脂質(zhì)過氧化,使血管內(nèi)皮功能受損,促進(jìn)心肌纖維化及心室重構(gòu),從而介導(dǎo)CMD的發(fā)生。過量ROS與炎癥細(xì)胞互相影響,形成氧化應(yīng)激-炎癥刺激的惡性循環(huán)。研究表明,有氧運(yùn)動訓(xùn)練刺激PPARβ/δ表達(dá),提高超氧化物歧化酶(SOD)表達(dá)來增強(qiáng)對氧化應(yīng)激的適應(yīng)[25],這種適應(yīng)性反應(yīng)涉及 NF-κB 、SOD、絲裂原活化蛋白激酶(MAPK)和PGC-1等因子,其中 NF-κB 是炎癥反應(yīng)和氧化應(yīng)激的關(guān)鍵核轉(zhuǎn)錄因子, NF-κB 促進(jìn)黏附分子和促炎因子的釋放,上調(diào)NLRP3炎性小體表達(dá)。運(yùn)動通過選擇性抑制 NF-κB 改善血流調(diào)節(jié)并減少全身炎癥[26]。此外,運(yùn)動通過上調(diào)Nrf2表達(dá)和抑制 Janus蛋白酪氨酸激酶2(JAK2)/信號轉(zhuǎn)導(dǎo)和轉(zhuǎn)錄激活子3(STAT3)級聯(lián)反應(yīng)[27]增強(qiáng)抗氧化能力,減少促炎信號。但也有報(bào)道稱,長期過度運(yùn)動會降低 Nrf2mRNA 的表達(dá)[28],且運(yùn)動過度也會增加ROS 的形成,并誘導(dǎo)急性期免疫反應(yīng)。
此外,運(yùn)動促進(jìn)骨骼肌分泌鳶尾素,血清鳶尾素水平升高與冠狀動脈粥樣硬化負(fù)擔(dān)減輕相關(guān)[29]。血清鳶尾素分泌水平可預(yù)測冠狀動脈狹窄的嚴(yán)重程度[30]。鳶尾素通過抑制ROS/p38MAPK/NF-kB信號通路減少白細(xì)胞和單核細(xì)胞對動脈壁表面的趨化黏附[31],上調(diào)抗凋亡蛋白(如Bcl-2)表達(dá)減輕氧化型低密度脂蛋白(ox-LDL)誘導(dǎo)的內(nèi)皮細(xì)胞凋亡。
近年來,研究發(fā)現(xiàn)外泌體(extracellularvesicles,EVs)分泌的內(nèi)容物miRNA調(diào)控運(yùn)動對心血管的益處。作為一種新型細(xì)胞間通信工具,EVs主要通過攜帶的內(nèi)容物調(diào)節(jié)多種生物過程,如細(xì)胞免疫應(yīng)答、炎癥反應(yīng)和細(xì)胞凋亡等。其中miRNA是一組由 20~22 個(gè)核苷酸組成的高度保守的非編碼RNA,其作用機(jī)制主要是通過與靶基因的 3′ 非翻譯區(qū)(UTR)結(jié)合,促進(jìn)基因沉默和抑制蛋白質(zhì)翻譯[32]。多種miRNA被證明參與了心肌肥大進(jìn)程,例如miRNA-17-3p、miRNA-124、miRNA-133和miRNA-144等核酸的表達(dá)間接調(diào)控PI3K/AKT/雷帕霉素靶蛋白(mTOR)信號通路。研究發(fā)現(xiàn),有氧運(yùn)動可通過調(diào)控miRNA表達(dá)介導(dǎo)心血管保護(hù)作用,例如運(yùn)動通過上調(diào)miR-574-3p和抑制IL-6/JAK/STAT通路,減輕心肌間質(zhì)纖維化的發(fā)生[33]。另外,有氧運(yùn)動上調(diào)miRNA-126表達(dá),通過MAPK和PI3K/Akt信號級聯(lián)反應(yīng)促進(jìn)血管生成。miRNA也被發(fā)現(xiàn)參與心肌細(xì)胞自噬的調(diào)控,運(yùn)動通過上調(diào)miRNA-188-3p水平來抑制自噬相關(guān)蛋白7(ATG7)翻譯,從而減輕心臟自噬「34],從而在預(yù)防發(fā)生心肌梗死中發(fā)揮重要作用,miRNA-210則在運(yùn)動介導(dǎo)BNIP3/NIX抑制線粒體自噬減輕心肌細(xì)胞損傷發(fā)揮作用[35]。體育鍛煉也會上調(diào)部分miRNA如miRNA-342-5p、miRNA-1192表達(dá),通過下調(diào)caspase-3來影響細(xì)胞抗凋亡作用,以及釋放miRNA-29b和miRNA-455促進(jìn)纖維化和肌細(xì)胞解偶聯(lián)[32]??傊?,miRNA在多個(gè)方面通過調(diào)控不同信號分子影響運(yùn)動所介導(dǎo)的心血管健康效應(yīng)。
4運(yùn)動康復(fù)恢復(fù)線粒體自噬水平
線粒體功能對于維持冠狀動脈微血管完整性起至關(guān)重要的作用。線粒體自噬水平過低或過高對冠狀動脈微血管均有不利影響:敲除ATG7的小鼠出現(xiàn)自噬水平過低[36],導(dǎo)致瘦素抵抗、血管收縮擴(kuò)張功能障礙和葡萄糖攝取降低;應(yīng)激條件下細(xì)胞自噬過度激活則介導(dǎo)細(xì)胞凋亡和線粒體功能障礙。研究發(fā)現(xiàn),運(yùn)動通過信號因子雙向、動態(tài)調(diào)節(jié)線粒體自噬水平及通量,恢復(fù)心臟正常自噬水平來清除受損線粒體[14,37]
線粒體質(zhì)量控制系統(tǒng)包括線粒體的生物發(fā)生、線粒體動力學(xué)和線粒體自噬,三者互相協(xié)調(diào),維持線粒體正常功能,其中線粒體自噬是指內(nèi)質(zhì)網(wǎng)來源的細(xì)胞囊泡選擇性吞噬受損或功能障礙的線粒體,通過與溶酶體融合降解來維持能量代謝和細(xì)胞穩(wěn)態(tài),PGC-1是線粒體生物發(fā)生的主要調(diào)節(jié)因子,與PPAR相互作用促進(jìn)脂肪酸氧化,與雌激素相關(guān)受體相互作用誘導(dǎo)血管形成[38]。目前認(rèn)為線粒體自噬的調(diào)控機(jī)制包括BNIP3/FUNDC1/NIX途徑和PINK1/Parkin途徑,其中FUNDC1介導(dǎo)的線粒體自噬通過 PGC-1∝/Nrf1 途徑與線粒體生物發(fā)生相互作用調(diào)節(jié)線粒體穩(wěn)態(tài),F(xiàn)UNDC1磷酸化Unc-51樣激酶1ser17位點(diǎn)(ULK1ser17)介導(dǎo)自噬體成熟,其LC3相互作用區(qū)(LIR)與LC3-Ⅱ相互作用進(jìn)行線粒體分解,BNIP3和NIX也通過LIR發(fā)揮作用[39]。PTEN誘導(dǎo)PINK1的積累誘導(dǎo)Parkin磷酸化,從而介導(dǎo)線粒體自噬,此過程受到Beclin-1、AMPK、線粒體融合蛋白2(Mfn2)等表達(dá)因子的調(diào)控。近期研究發(fā)現(xiàn),Nrf1和Nrf2的敲除均會導(dǎo)致細(xì)胞ROS水平升高,但敲除Nrf1后細(xì)胞氧化損傷程度明顯高于Nrf2的敲除,且由于Nrf1缺失而增加的ROS水平并沒有因?yàn)镹rf2的急劇升高而清除,激活 Nrf1可能是治療心血管疾病的重要潛在靶點(diǎn)[40] 。
研究發(fā)現(xiàn),運(yùn)動訓(xùn)練通過激活A(yù)MPK/PGC-1a途徑增加高脂肪飲食小鼠骨骼肌自噬通量,調(diào)節(jié)內(nèi)質(zhì)網(wǎng)應(yīng)激,減輕胰島素抵抗[41],同時(shí)長期運(yùn)動通過干預(yù)Nrf2來調(diào)節(jié)多種線粒體酶激活PGC-1,并誘導(dǎo)受損線粒體被自噬體選擇性吞噬。CHEN等[42]發(fā)現(xiàn)運(yùn)動通過激活I(lǐng)GF1/PI3K/AKT1/mTOR信號通路抑制自噬促進(jìn)心肌細(xì)胞蛋白合成,從而介導(dǎo)心臟生理性肥厚,同時(shí)觀察到運(yùn)動顯著上調(diào)VEGF和 HIF-1α 基因表達(dá)誘導(dǎo)血管生成。JIANG等[43]發(fā)現(xiàn)5周的有氧運(yùn)動訓(xùn)練可以減輕缺血再灌注引起的小鼠心肌損傷,增加線粒體自噬相關(guān)蛋白BNIP3、LC3-Ⅱ和熱休克蛋白70(HSP70)的表達(dá),增強(qiáng)抗應(yīng)激能力。PAQR-1/AdipoR1信號與運(yùn)動延緩小鼠年齡相關(guān)的肌肉細(xì)胞衰老密切相關(guān)[44],另外運(yùn)動訓(xùn)練和二氮氧化物通過增加ATP敏感的鉀通道(KATPchannel)表達(dá)降低ROS水平,改善呼吸和促進(jìn)脂肪酸 β 氧化來防止線粒體功能障礙。
此外,鳶尾素通過AMPK/PGC- ??1∝ 信號通路介導(dǎo)Nrf 、線粒體轉(zhuǎn)錄因子A(Tfam)和UCP2的表達(dá),抑制線粒體分裂相關(guān)動力蛋白1(Drp1),恢復(fù)視神經(jīng)萎縮1(Opa1)和Mfn2的表達(dá),減少線粒體過度裂變和促進(jìn)線粒體融合,從而維持線粒體穩(wěn)態(tài)[45]
不同強(qiáng)度的運(yùn)動訓(xùn)練對線粒體自噬水平的影響不同,例如在缺血性心力衰竭小鼠中,高強(qiáng)度間歇訓(xùn)練(HIIT)比中強(qiáng)度連續(xù)訓(xùn)練(MICT)更能促進(jìn)線粒體自噬,而MICT則與壓力過載心力衰竭顯著改善相關(guān)[46]。值得注意的是,過度運(yùn)動會上調(diào)心肌細(xì)胞線粒體自噬水平,導(dǎo)致心肌細(xì)胞壞死凋亡,應(yīng)用自噬抑制劑3-甲基腺嘌呤(3-MA)一定程度上可減輕心肌損傷。不同運(yùn)動強(qiáng)度及時(shí)間對線粒體自噬水平的影響機(jī)制尚需進(jìn)一步探索。
5運(yùn)動康復(fù)改善脂質(zhì)分布及胰島素抵抗
肥胖、胰島素抵抗等危險(xiǎn)因素導(dǎo)致毛細(xì)血管通透性異常、微動脈瘤形成、細(xì)胞外基質(zhì)過度沉積和動脈周圍纖維化,從而引起冠狀動脈微血管結(jié)構(gòu)改變[19]。運(yùn)動可改善脂質(zhì)分布及胰島素抵抗從而改善冠狀動脈微循環(huán)。
在人體內(nèi),脂肪組織分為3種表型:白色脂肪組織(WAT)、棕色脂肪組織(BAT)和介于WAT與BAT之間的米色脂肪組織[47],脂肪組織將體內(nèi)的脂肪以脂滴(LD)的形式儲存在細(xì)胞內(nèi),當(dāng)體內(nèi)脂肪量超出LD的存儲能力時(shí),脂肪細(xì)胞增生肥大,招募巨噬細(xì)胞極化為M1型,釋放游離脂肪酸和有毒脂質(zhì)(如神經(jīng)酰胺、二酰基甘油),出現(xiàn)異位脂肪沉積、脂肪組織微環(huán)境改變及脂肪毒性,使內(nèi)質(zhì)網(wǎng)等細(xì)胞器功能失調(diào)并進(jìn)一步釋放ROS和炎癥因子,促進(jìn)胰島素抵抗、瘦素抵抗、脂肪組織纖維重塑和全身慢性低度炎癥的發(fā)展[48],其機(jī)制與PPAR- γ 、MAPK、JNK信號通路以及Toll樣受體4等有關(guān)。肥胖與胰島素抵抗存在因果關(guān)系,高脂飲食誘導(dǎo)的胰島素抵抗與高胰島素血癥與冠狀動脈血管硬化密切相關(guān)[49]。研究發(fā)現(xiàn)運(yùn)動可改善肥胖大鼠脂肪組織的胰島素抵抗和LD面積大小[50],其機(jī)制可能與脂聯(lián)素水平升高、改善內(nèi)質(zhì)網(wǎng)應(yīng)激及瘦素抵抗等有關(guān)。QIU等[51]發(fā)現(xiàn)有氧運(yùn)動通過信號級聯(lián)反應(yīng)在增加小鼠心臟葡萄糖利用率和脂肪酸氧化水平等方面發(fā)揮重要作用。運(yùn)動也可以調(diào)節(jié)LD在骨骼肌線粒體不同區(qū)域數(shù)量分布:例如12周運(yùn)動訓(xùn)練(MICT、HIIT)可增加肥胖成年人骨骼肌細(xì)胞肌纖維間線粒體(IMF)區(qū)域LD數(shù)量,以支持運(yùn)動期間最高能量消耗部位附近的線粒體能量需求「52],且運(yùn)動訓(xùn)練可能通過降低肌肉細(xì)胞肌膜下線粒體(SS)區(qū)域脂質(zhì)含量或LD大小來減輕肥胖患者的胰島素抵抗[53]。最近一項(xiàng)研究發(fā)現(xiàn),高脂飲食的雄性小鼠腹股溝WAT表型中的線粒體由于受到小GTP酶RalA激活而發(fā)生線粒體碎片化,其線粒體融合標(biāo)志物表達(dá)降低,線粒體裂變相關(guān)蛋白的表達(dá)顯著增加「54],表明肥胖人群線粒體生物發(fā)生受損。研究發(fā)現(xiàn),不論是MICT、HIIT還是抗阻運(yùn)動均可靶向促進(jìn)線粒體動力學(xué),改善線粒體抗氧化能力,調(diào)節(jié)線粒體生物發(fā)生[55]。另外,腸道微生物及其代謝物功能失衡與肥胖相關(guān)代謝功能障礙存在聯(lián)系[48],有氧運(yùn)動訓(xùn)練可以調(diào)節(jié)腸道微生物群豐度和群落結(jié)構(gòu),改變微生物菌群的療法或許可以為預(yù)防和管理心血管疾病帶來新的方法。
6運(yùn)動康復(fù)調(diào)節(jié)血管周圍脂肪組織(perivascularadiposetissue,PVAT)功能障礙
PVAT作為一種特殊類型的脂肪貯存庫,與相鄰血管壁之間存在復(fù)雜雙向影響作用。功能障礙的PVAT旁分泌、內(nèi)分泌各種生物活性成分調(diào)控血管炎癥、氧化應(yīng)激和血管收縮舒張障礙的發(fā)生,促進(jìn)動脈粥樣硬化,對心臟微血管產(chǎn)生不利影響[56]。研究發(fā)現(xiàn),運(yùn)動通過控制脂肪細(xì)胞表型轉(zhuǎn)化介導(dǎo)PVAT功能的恢復(fù)。
生理狀態(tài)下,PVAT分泌脂聯(lián)素、VEGF、NO、網(wǎng)膜素、WNT5a等舒張血管的脂肪因子[4-55],以及血管生成素1-7(Ang1-7)、IL-4、IL-18及神經(jīng)調(diào)節(jié)素4(NRG4)等抗炎因子來維持血管功能。病理狀態(tài)下功能障礙的PVAT則上調(diào)瘦素和ROS產(chǎn)生來促進(jìn)血管炎癥和氧化應(yīng)激發(fā)生。此外PVAT中含有各種免疫細(xì)胞群落(如淋巴細(xì)胞、巨噬細(xì)胞、肥大細(xì)胞等)「57],在健康狀態(tài)下一同參與PVAT對血管壁的抗炎、抗氧化、抗纖維化和抗收縮作用。PVAT是WAT、BAT和米色脂肪組織的混合型,在病理狀態(tài)下發(fā)生表型的變化:肥胖和高脂飲食通過AMPK、mTOR、RAAS系統(tǒng)等機(jī)制增加PVAT體積,使其形成WAT樣表型,促進(jìn)UCP-1低表達(dá)和低線粒體數(shù)量,誘導(dǎo) PVAT功能障礙[57-59]。血管細(xì)胞與 PVAT之間相互作用、雙向通訊。血管氧化應(yīng)激時(shí),血管壁分泌4-羥基壬烯醛(4-HNE)擴(kuò)散到PVAT中,激活脂肪細(xì)胞中的PPAR- γ 受體,PVAT體積變小并轉(zhuǎn)變?yōu)锽AT樣表型,導(dǎo)致脂聯(lián)素、瘦素等血管松弛因子分泌上調(diào),從而對抗血管氧化損傷。同樣,PVAT脂肪細(xì)胞作為“生物傳感器”感知血管壁分泌的炎癥分子,淋巴細(xì)胞轉(zhuǎn)化為Th1細(xì)胞,促進(jìn)血管新生內(nèi)膜的形成和炎癥因子釋放,導(dǎo)致血管壁硬化和血管炎癥[60]。研究發(fā)現(xiàn),運(yùn)動可以改善PVAT功能障礙引起的動脈僵硬和細(xì)胞外基質(zhì)重塑[6],促進(jìn)舒張血管的松弛因子釋放,減輕促炎因子表達(dá)。此外,運(yùn)動訓(xùn)練減輕對肥胖大鼠高脂飲食誘導(dǎo)的脂肪白化脂肪酸結(jié)合蛋白4(FABP4)水平下調(diào)工,同時(shí)促進(jìn)脂肪組織褐變(UCP1水平上升),且運(yùn)動訓(xùn)練使高脂肪飲食大鼠組的血清瘦素水平降低、脂聯(lián)素濃度和 表達(dá)水平升高,顯著降低肥胖大鼠PVAT中LD面積的大小〔59],同時(shí)運(yùn)動使得脂肪細(xì)胞中BMP4蛋白過度表達(dá)激活下游Smads和p38/MAPK信號通路,促進(jìn)PVAT的褐變。SHI等[6]對心力衰竭小鼠模型進(jìn)行6周有氧運(yùn)動訓(xùn)練后發(fā)現(xiàn)運(yùn)動可以提高PVAT脂聯(lián)素水平和減輕交感神經(jīng)過度興奮。未來PVAT或許將是動脈疾病的預(yù)測因子和治療靶點(diǎn)。
7小結(jié)
運(yùn)動康復(fù)在表觀上可調(diào)節(jié)瘦素抵抗、胰島素抵抗、肥胖等心血管危險(xiǎn)因素,并通過不同的信號分子激活或抑制多層信號級聯(lián)反應(yīng),在各細(xì)胞間進(jìn)行細(xì)胞間信號通信,實(shí)現(xiàn)對炎癥因子釋放、內(nèi)質(zhì)網(wǎng)應(yīng)激、線粒體功能障礙、心肌細(xì)胞凋亡及病理性肥厚等多方面的調(diào)控。有規(guī)律的有氧運(yùn)動已被證明有益于冠狀動脈微血管功能恢復(fù)并降低總體疾病死亡率。但相關(guān)的臨床實(shí)驗(yàn)受限于樣本量低、人組和診斷標(biāo)準(zhǔn)不一以及終點(diǎn)指標(biāo)不同等原因?qū)е聦?shí)驗(yàn)結(jié)果有較大差異,運(yùn)動對冠狀動脈微循環(huán)帶來健康效益的分子機(jī)制仍在探索中,未來需要更多循證醫(yī)學(xué)數(shù)據(jù)來驗(yàn)證和優(yōu)化CMD的運(yùn)動康復(fù)方案。
作者貢獻(xiàn):高桂英負(fù)責(zé)文章的構(gòu)思與設(shè)計(jì)、研究資料的收集與整理、論文撰寫;胡陽負(fù)責(zé)論文的設(shè)計(jì)、撰寫進(jìn)度把控;張世益負(fù)責(zé)論文修訂及撰寫;孟怡負(fù)責(zé)論文的編輯、整理;鄧潔負(fù)責(zé)文章的質(zhì)量控制及審校、對文章整體負(fù)責(zé),監(jiān)督管理。
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高桂英D https://orcid.org/0009-0008-1873-3284
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