运动因子对心血管的保护作用

Protective effects of exerkine on cardiovascular system

摘要

心血管疾病(cardiovascular disease，CVD)严重威胁人类生命健康。运动对于CVD的防治至关重要，是CVD非药物疗法的重要手段之一。运动可调控组织和细胞分泌运动因子的水平，作用于心血管或通过改善心血管危险因素，直接或间接发挥心血管保护作用。镍纹蛋白样蛋白(meteorin-like protein，Metrnl)、脑源性神经营养因子(brain-derived neurotrophic factor，BDNF)、成纤维细胞生长因子21(fibroblast growth factor 21，FGF21)和外泌体中的微RNA(microRNA，miRNA)等运动因子对于动脉粥样硬化、心力衰竭、心脏缺血后再灌注和心肌梗死等CVD及其危险因素具有重要的调节作用。探究Metrnl、BDNF、FGF21和外泌体miRNA等运动因子发挥心血管保护作用的相关信号通路及机制有助于为运动防治CVD提供新思路。

Abstract

Cardiovascular disease (CVD) poses a serious threat to human health. Exercise plays an important role in both the prevention and treatment of CVD and is one of the key non-pharmacological interventions. Exercise can regulate the level of exerkine secreted by different tissue cells, directly affect the cardiovascular system or play a role in cardiovascular protection by improving cardiovascular risk factors. Exerkine such as meteorin-like protein (Metrnl), brain-derived neurotrophic factor (BDNF), fibroblast growth factor 21 (FGF21), and exosomal microRNA (miRNA) play an important role in regulating vascular and cardiac diseases such as atherosclerosis, heart failure, cardiac ischemia-reperfusion and myocardial infarction, as well as their risk factors. Exploring the signaling pathways and mechanisms by which Metrnl, BDNF, FGF21, and exosomal miRNAs exert cardiovascular protective effects can provide novel insights into exercise-based strategies for preventing and treating cardiovascular diseases.

关键词

心血管 / 运动因子 / 镍纹蛋白样蛋白 / 脑源性神经营养因子 / 成纤维细胞生长因子21 / 外泌体微RNA

Key words

cardiovascular / exerkine / meteorin-like protein / brain-derived neurotrophic factor / fibroblast growth factor 21 / exosomal miRNA

心血管疾病(cardiovascular disease，CVD)是威胁人类生命和健康的重大公共卫生问题。世界卫生组织(World Health Organization，WHO)数据显示每年约有1 790万人死于CVD，约占全球死亡总人数的32%。中国CVD患病率处于持续上升的阶段，现患人数约3.3亿^[1]。维护心血管健康、防治CVD刻不容缓。CVD多源于吸烟、高血压、血脂异常和糖尿病等危险因素导致的血管内皮细胞、心肌细胞功能障碍^[2-3]。经常进行体育锻炼在CVD的一级和二级预防中发挥着重要作用^[4]。体育锻炼与CVD病死率成反比，对减少CVD的发病风险有显著的效果。WHO指南^[5]推荐成年人每周应至少进行150~300 min中等强度有氧运动；或者至少75~150 min的高强度有氧运动；或二者结合，以获得更显著的健康益处。指南^[5]还表明，尽管未达到推荐标准，进行一些体育活动也会对健康有益。与传统的药物干预相比，运动具有易于开展、低成本的特点，可降低患者整个生命周期的医疗成本和提高患者生活质量。尽管运动的保护作用已经得到证实，但运动对心血管系统影响的分子机制仍在研究中。Safdar等^[6]提出机制与运动诱导的骨骼肌和其他器官释放多肽和核酸有关。运动因子(exerkine)是在急性和/或慢性运动中释放的信号分子，通过内分泌、旁分泌和/或自分泌途径发挥作用。许多器官、组织和细胞释放这些因子，包括骨骼肌(肌肉因子)、心脏(心脏因子)、肝(肝因子)、脂肪组织(脂肪因子)和神经元(神经因子)等^[7]。多种运动因子如镍纹蛋白类似物(meteorin-like，Metrnl)、脑源性神经营养因子(brain-derived neurotrophic factor，BDNF)、成纤维细胞生长因子21(fibroblast growth factor 21，FGF21)和外泌体中的微RNA(microRNA，miRNA)可减少氧化应激、抗动脉粥样硬化、改善血管内皮功能、减轻心肌缺血和再灌注损伤、增强心肌收缩力，发挥预防和改善CVD的积极作用，保护心血管健康。本文旨在总结运动因子介导心血管的保护作用及其机制的最新研究进展。

1 Metrnl的心血管保护作用

Metrnl(又名Cometin、Subfatin等)是一种循环因子^[8]，运动和寒冷刺激可诱导其在骨骼肌、脂肪中表达增加^[9-10]。Metrnl在改善代谢、内皮功能和动脉粥样硬化方面发挥重要作用，与冠状动脉疾病(coronary artery disease，CAD)的发生和严重程度显著相关^[11-13]。Metrnl通过骨骼肌细胞中钙依赖性腺苷酸活化蛋白激酶(adenosine monophosphate activated protein kinase，AMPK)α2途径增加葡萄糖摄取，并以AMPKa2依赖性方式促进葡萄糖转运蛋白4(glucose transporter 4，GLUT4)的转录抑制因子——组蛋白去乙酰化酶5(histone deacetylase 5，HDAC5)磷酸化，从而激活GLUT4的转录和由细胞内转位至细胞膜，增加葡萄糖摄取，改善葡萄糖代谢^[14](表1)。血糖水平的升高，即使未达到糖尿病标准，也会显著影响CVD的发生风险^[15]。Metrnl通过AMPKα2改善葡萄糖代谢，进而对心血管产生保护作用。研究^[10]发现Metrnl的心脏特异性过表达明显改善了糖尿病小鼠的心脏损伤和功能障碍。Metrnl通过肝激酶B1(liver kinase B1，LKB1)/AMPK/Unc-51样自噬激活激酶1(Unc-51 like autophagy activating kinase 1，ULK1)依赖性机制抑制了心肌细胞中的环鸟苷酸-腺苷酸合成酶(cyclic GMP-AMP synthase，cGAS)/干扰素基因刺激因子(stimulator of interferon genes，STING)信号转导，激活自噬途径。cGAS-STING通路可调控代谢性CVD不良结局的发生，并加速其恶化^[16]。Metrnl诱导的ULK1磷酸化促进了STING的去磷酸化和线粒体转位，随后STING与肿瘤坏死因子受体相关因子2(tumor necrosis factor receptor-associated factor 2，TRAF2)相互作用；TRAF2是一种支架蛋白和E3泛素连接酶，负责STING的泛素化和降解，使心肌细胞对自噬激活敏感(表1)。Metrnl是心肌梗死后血管生成的驱动因子，也是干细胞受体KIT(KIT受体酪氨酸激酶)的高亲和力配体。Metrnl通过KIT依赖性信号通路介导人内皮细胞的血管生成效应^[17](表1)。Metrnl是运动与活性氧(reactive oxygen species，ROS)产生减少、炎症减轻以及CAD患者功能改善之间联系的“桥梁”。CAD患者进行12周的中等强度持续运动后Metrnl水平显著增加，且白细胞介素-1β(interleukin-1-beta，IL-1β)和肿瘤坏死因子-α(tumor necrosis factor-alpha，TNF-α)水平显著降低^[18]。研究^[19]发现，Metrnl通过增加有氧呼吸和减少氧化应激来减轻内皮代谢功能障碍，通过下调ROS-NOD样受体热蛋白结构域蛋白3(NOD-like receptor pyrin domain containing 3，NLRP3)信号通路来减轻内皮炎症反应(表1)。NLRP3与CVD有关，特别是动脉粥样硬化，Metrnl通过减少NLRP3激活，从而减轻CAD的不良影响。内皮功能障碍是动脉粥样硬化最早可识别的症状之一^[20]，内皮Metrnl缺乏导致血管内皮功能障碍，包括通过降低内皮型一氧化氮合酶(endothelial nitric oxide synthase，eNOS)Ser1177位点的磷酸化损害内皮依赖性血管舒张，外源性Metrnl可以恢复由Metrnl缺乏引起的内皮功能障碍。这些发现揭示了Metrnl通过调节血管内皮功能以维持心血管健康^[21]。

多种组织细胞能表达Metrnl，包括骨骼肌、脂肪细胞、巨噬细胞和内皮细胞。运动可显著提高各肌肉库中Metrnl的表达，肌肉分泌的Metrnl可能通过组织间的串扰对不同组织产生作用^[18]。但运动训练是否能刺激其他组织细胞Metrnl的表达，以及不同组织来源的Metrnl在功能上是否相同目前尚不清楚，有待在未来进一步进行研究。

2 BDNF的心血管保护作用

BDNF是神经营养素家族的组成之一，BDNF主要由神经元和胶质细胞合成^[22]。运动可以增加脑内BDNF的表达^[23]，BDNF可能是运动改善心血管健康的重要介导因素^[24]。大脑中的BDNF可以通过血脑屏障进入外周血液，通过多种机制对心血管发挥保护作用。前瞻性调查^[25]发现血清BDNF越高，CVD和死亡风险越低。

BDNF与心肌细胞存活和功能恢复相关。BDNF增强心肌细胞功能，BDNF/原肌球蛋白受体激酶B(tropomyosin receptor kinase B，TrkB)通过以钙/钙调素依赖性蛋白激酶Ⅱ(Ca/calmodulin dependent protein kinase Ⅱ，CaMKⅡ)依赖性方式直接调节Ca²⁺循环，进而诱导心肌功能增强(表1)。BDNF/TrkB信号转导是周围神经系统控制心肌生理的一种方式^[26]。上调BDNF可以减少心肌梗死中的梗塞面积并改善心功能，对心肌细胞凋亡有细胞保护作用。急性心肌梗死时BDNF/TrkB/瞬时受体电位通道(transient receptor potential channel，TRPC)轴被激活，TPRC3/6通道参与BDNF对心细胞凋亡的保护作用，BDNF通过上调缺血心肌中抗凋亡蛋白B淋巴细胞瘤-2(B-cell lymphoma-2，Bcl-2)的表达和下调Caspase3的表达来抑制心肌细胞凋亡^[27](表1)。BDNF还能调节miRNA的水平。缺血心肌细胞中miR-195的上调可通过靶向Bcl-2促进缺血细胞凋亡；BDNF可减轻miR-195在心肌细胞中的促凋亡作用^[28]。这些发现表明BDNF/miR-195/Bcl-2轴可能有助于减少心肌缺血性损伤(表1)。研究^[29]发现，上调BDNF和蛋白激酶B(protein kinase B，AKT)/哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin，mTOR)轴失活可促进急性心肌梗死大鼠心肌细胞自噬(表1)。自噬是细胞维持正常功能的一种方式，是细胞应对外界压力和挑战的重要机制。

BDNF在抗心力衰竭中也发挥作用。研究^[30]发现，BDNF-TrkB信号轴介导心肌梗死后运动对心功能恢复的机制，心肌梗死后运动训练可改善心脏射血分数和左心室舒张末压，增加每搏输出量和心指数，这些改善可能是通过抑制非梗死区域成熟BDNF(mBDNF)、磷酸化CaMKⅡ(p-CaMKⅡ)和磷酸化AKT(p-AKT)的表达，通过BDNF-TrkB轴及其下游效应因子CaMKⅡ和AKT发挥作用，改善心脏收缩和舒张功能。BDNF还具有神经保护作用，它在心肌缺血和再灌注后心脏感觉和交感神经元功能的改变中发挥作用^[31]。

运动可刺激内皮BDNF表达，促血管生成。BDNF可以成为内皮功能和心血管健康之间的新联系^[32]。BDNF可通过激活BDNF-TrkB-FL-磷脂酰肌醇3-激酶(phosphatidylinositol 3 kinase，PI3K)/AKT通路促进年轻心脏微血管内皮细胞(cardio microvascular endothelial cells，CMECs)迁移，这可能有利于心肌梗死后的血管生成^[33](表1)。然而，CMECs衰老导致其受体TrkB亚型的表达发生变化：3个亚型(TrkB-FL、TrkB-T1和TrkB-T2)中，只有截短型TrkB(TrkB-T1)在衰老的CMECs中继续表达，BDNF仍然能继续发挥作用。衰老的CMECs通过BDNF-TrkB-T1信号通路募集Willin[又称FERM结构域蛋白6(FERM domain-containing protein 6，FRMD6)]作为下游效应因子，进一步上调Hippo通路的关键元件。这促进了yes相关蛋白(yes-associated protein，Yap)的去磷酸化及去磷酸化的Yap转位进入细胞核，从而激活Hippo通路，促进衰老CMECs的迁移^[34](表1)。BDNF可增加krüppel样因子2(krüppel-like factor 2，KLF2)并下调己糖激酶1(hexokinase 1，HK1)，KLF2与HK1相互作用，KLF2的增加能缓解HK1介导的糖代谢异常，进而可抑制糖尿病内膜钙化^[35](表1)。

在对BDNF基因的研究^[36-37]中发现，人群中一部分人存在BDNFVal66Met突变，尽管BDNFVal66Met与肥胖、血栓形成和心肌梗死有关，但通过生活方式改变，尤其是运动，对管理与特定BDNFVal66Met突变相关的肥胖相关的动脉血栓形成和炎症具有很强的影响。

运动可以增加骨骼肌中的BDNF，参与骨骼肌中线粒体生物合成和脂肪酸氧化^[38-39]。但骨骼肌分泌的BDNF是否进入血液，直接参与对心血管的作用目前尚存在争议，需要更多的研究来进一步明确这一途径。

3 FGF21的心血管保护作用

FGF21是一种由208个氨基酸组成的信号蛋白质，属于成纤维细胞生长因子家族。FGF21因其在调节糖脂稳态及能量代谢方面的多重作用而备受关注^[40]。FGF21在肝、白色脂肪组织、棕色脂肪组织、肌肉、胰腺、心脏和大脑中都有表达^[41]。FGF21可在各种应激条件下表达，如冷暴露、营养失衡、运动和一些病理条件。FGF21作为一种潜在的生物标志物，在调节心血管健康和改善CVD中也发挥重要作用。

运动可增加血清FGF21的水平，血清FGF21主要来源于肝。运动也可引起FGF21通过AKT依赖途径在骨骼肌中合成并分泌，介导自分泌和内分泌作用^[42]。FGF21也可因运动引起的心脏应激反应而在心脏中分泌，通过自分泌环发挥其心脏保护作用^[43]。FGF21在运动引起的抗心肌纤维化和心功能改善方面发挥重要作用。此外，运动可诱导成纤维细胞生长因子受体(fibroblast growth factor receptor，FGFR)1及其受体复合物表达上调，增加组织对FGF21的敏感性^[44]。因此，FGF21可能是运动与心血管健康之间的一种重要介质。

FGF21通过调节糖脂代谢和能量消耗，降低心血管危险因素，进而发挥心血管保护作用。运动诱导肝FGF21表达增加从而上调血液FGF21水平可能有助于改善全身葡萄糖耐量^[45]。研究^[46]表明，运动训练可使小鼠循环中FGF21增加，心脏FGF21的mRNA和蛋白质增多，上调棕色脂肪中参与产热和脂肪酸氧化的FGF21靶基因；FGF21通过刺激棕色脂肪组织中的产热和脂质氧化，改善全身代谢稳态。在对小鼠进行8周的跑转轮运动后，运动引起的代谢改善可通过过氧化物酶体增殖物活化受体-α(peroxisome proliferator-activated receptor alpha，PPARα)-FGF21-FGFR1机制持续存在^[47]。肝脂肪堆积会增加患心脏代谢疾病的风险，并且肝脂肪堆积会导致肝抵抗FGF21，阻碍FGF21发挥作用。而运动可通过刺激肌肉中FGF21的合成，通过AMPK依赖途径分泌到血液循环中，促进肝的脂肪吞噬^[48](表1)。一项针对肥胖2型糖尿病男性患者的随机对照试验^[49]结果显示，有氧运动和抗阻运动都能改善其FGF21水平，且抗阻运动表现出更实质性的适应性反应，可能是抗阻运动诱导FGF21活化，进而增强肌肉中的胰岛素作用，从而改善AMPK活性及其上游的葡萄糖代谢。FGF21刺激线粒体生成，增加肌原纤维的氧化能力，改善全身葡萄糖稳态。

FGF21也可直接作用于心肌细胞，调节心脏功能。运动训练上调FGF21的蛋白质表达，FGF21使转化生长因子β1(transforming growth factor-beta 1，TGF-β1)-果蝇母本抗生存因子蛋白2/3(small mother against decapentaplegic protein 2/3，Smad2/3)-基质金属蛋白酶2/9(matrix metalloproteases 2/9，MMP2/9)信号通路失活，减轻心肌梗死小鼠心脏功能障碍和心肌纤维化^[50](表1)。该研究还探究了不同类型的运动训练对正常和心肌梗死小鼠的FGF21蛋白质表达、心脏功能和组织学变化的影响，发现有氧和抗阻运动均能上调心肌梗死小鼠心脏FGF21蛋白质表达，减轻心肌纤维化和心功能障碍。FGF21也在糖尿病和心脏病中发挥保护作用，运动增强FGF21对心脏的作用，通过AMPK诱导的叉头框蛋白O3(forkhead box O3，FOXO3)磷酸化诱导线粒体沉默信息调节因子(silent information regulator，SIRT)3的表达，从而逆转糖尿病诱导的线粒体酶超乙酰化和功能损伤，提高心脏线粒体酶的活性，减轻糖尿病诱导的心脏功能障碍^[51](表1)。

FGF21在抗动脉粥样硬化、缓解血管紧张素Ⅱ相关的高血压和血管损伤、抗氧化应激、抗心律失常方面也发挥重要作用。目前研究发现了FGF21的多种保护机制：1)增加脂联素水平^[52]；2)通过活化C激酶受体1(receptor for activated C kinase 1，Rack1)介导的AMPK激活和自噬蛋白(autophagy protein，ATG)5相互作用，诱导自噬，促进胆固醇排出，减少胆固醇在泡沫细胞中的积累，从而发挥抗动脉粥样硬化作用^[53]；3)通过激活血管紧张素转换酶2(angiotensin converting enzyme 2，ACE2)/血管紧张素(1-7)轴预防血管紧张素Ⅱ诱导的高血压和血管损伤^[54]；4)与SIRT1相互作用诱导超氧化物歧化酶2(superoxide dismutase 2，SOD2)、解偶联蛋白(uncoupling protein，UCP)2、UCP3等抗氧化基因的表达，从而减少ROS的产生^[55-56]；5)通过FGFR保护心脏跨膜离子通道，改善心肌细胞电生理功能，减少梗死后心律失常^[57](表1)。但是这些通路与运动的关系尚不清楚，运动诱导FGF21是否也发挥这些作用还需进一步探讨。

FGF21在心血管系统中发挥重要作用，但是上述研究大多是基于小鼠及病理条件下的作用，需要更多人体的研究。有研究^[58]显示心脏中的FGF21在健康心脏的能量代谢中并不起主要作用，但可能在患病心脏中发挥重要的保护作用。因此，FGF21可能在慢性病患者的运动干预中介导运动对慢性病的改善作用，这可能是慢性病患者运动干预的重要靶点。

4 外泌体miRNA的心血管保护作用

细胞外囊泡(extracellular vesicle，EV)是膜囊泡，携带生物活性分子，如蛋白质、脂质、DNA和miRNA，并将其释放到靶细胞中，有助于调节各种生理和病理过程^[59]。EV主要分成3类：外泌体、微泡和凋亡小体，miRNA一般在外泌体中。运动是促进EV产生的一种刺激因素，EV在运动后富含大量心脏保护介质。因此，外泌体释放的miRNA可能介导运动与健康改善。miRNA作为运动因子，在胚胎干细胞发育、肌生成和底物代谢等多种生理情况下具有调节转录后基因表达的作用，促进器官之间的串扰，协调运动的多系统益处^[60-63]。miRNA在调节各种运动适应中发挥着不可或缺的作用，包括线粒体生物发生、心肌重塑、外周肌肉血管生成、肌肉肥大、收缩力增强和底物代谢^[6]。

miRNA可减少心肌缺血的再灌注损伤。研究^[64]发现miR-342-5p是一种具有心脏保护作用的新型运动因子。为期4周的游泳训练可保护大鼠心脏免受心肌缺血/再灌注损伤，而miR-342-5p是这一过程的关键因子。内皮细胞是运动诱导的miR-342-5p的主要来源。miR-342-5p通过靶向心肌细胞中的Caspase9和c-Jun氨基末端激酶2(Jun Nterminal kinase 2，JNK2)发挥抗心肌细胞凋亡作用，其中Caspase9和JNK2既参与缺血和再灌注损伤，又参与细胞凋亡途径。miR-342-5p还通过靶向磷酸酶基因——Mg²⁺/Mn²⁺依赖性蛋白磷酸酶1F(protein phosphatase Mg²⁺/Mn²⁺-dependent 1F，PPM1F)增强生存信号(p-AKT)，AKT和胞外信号调节激酶(extracellular signal-regulated kinase，ERK)1/2是心脏保护的关键分子(表1)。长期运动诱导的miR-342-5p具有持续的心脏保护作用。

部分miRNA还发挥促进血管生成的作用。研究^[65]发现：运动可促进骨骼肌来源的miR-125a-5p分泌，促进血管生成和灌注恢复。miR-125a-5p通过靶向内皮素转化酶1(endothelin converting enzyme 1，ECE1)激活AKT/eNOS下游信号通路促进运动诱导的血运重建(表1)。运动通过上调肝源性细胞外囊泡miR-122-5p进而靶向内皮细胞中的1-酰基甘油-3- 磷酸O-酰基转移酶1(1-acylglycerol-3-phosphate O-acyltransferase 1，AGPAT1)增强脂肪酸利用，从而促进血管生成(表1)。脂肪酸氧化是核苷酸合成所必需的，脂肪酸代谢在血管生成中具有重要作用^[66]。

miRNA对内皮细胞和神经细胞具有一定的保护作用。适度运动可刺激内皮祖细胞外泌体释放miR-126并上调miR-126表达，有效减少高糖和缺氧引起的内皮细胞凋亡，其机制可能是调节出芽相关蛋白-1(sprouty-related protein-1，SPRED1)和血管内皮生长因子(vascular endothelial growth factor，VEGF)表达(表1)，SPRED1也可以调节VEGF的表达，VEGF作为重要的血管生成因子，具有抗凋亡作用，可防止内皮细胞死亡^[67]。运动提高miR-126水平还可改善缺氧损伤的N2a细胞的活力，对小鼠缺血性中风产生有益影响^[68]。此外，内皮祖细胞外泌体释放的miR-126还在改善心肌纤维化中发挥重要作用^[69]。miR-27a是最有效的神经血管保护性miRNA之一，运动干预提高内皮祖细胞外泌体miR-27a，改善了Neuro-2a(N2a)细胞的线粒体功能^[70]。长期运动诱导的外泌体 miR-532-5p通过下调肝配蛋白A型受体4(ephrin type A receptor 4，EPHA4)改善小鼠血脑屏障功能^[71](表1)。

miRNA还介导运动对糖尿病患者的心脏保护作用。研究^[72]表明，高强度间歇训练诱导的外泌体miRNA通过下调小鼠肝叉头框蛋白O1(forkhead box O1，FOXO1)来改善胰岛素敏感性。FOXO1是miR-133家族miRNA的直接靶点，miR-133b在体外和体内均可调节肝糖异生(表1)。miR-29b和miR-455下调基质金属蛋白酶9(matrix metalloproteases 9，MMP9)的水平，并防止MMP9导致纤维化和肌细胞解偶联的下游有害影响，这可能是运动对糖尿病患者心脏益处的机制之一^[73](表1)。

关于外泌体及其miRNA的研究逐渐增多。运动引起的外泌体miRNA水平变化似乎因人而异，在长期运动者中似乎更高^[74]。不同的细胞，不同的激活状态下，外泌体释放的miRNA也不同^[75]。有趣的是，自行车和跑步至力竭后恢复期miRNA的变化有一定差异，自行车运动后即刻miRNA显著增加，但持续时间相对较短，在其后的90 min休息时间内恢复至安静水平；跑步运动后即刻miRNA的增加幅度较小，但持续时间较长^[76]，这可能是跑步与更高的心率和更高的肌肉离心负荷有关，可能对组织稳态的挑战更大，需要更明显的级联修复。这2种运动后miRNA变化的差异值得进一步探讨。衰老会损害外泌体和miRNA在循环系统和骨骼肌细胞中的生物发生和释放，改变骨骼肌的细胞间通讯，抗阻运动可能有益于使与衰老相关的细胞间通讯改变正常化^[77]。

5 结语与展望

Metrnl、BDNF、FGF21和外泌体miRNA等运动因子对心血管发挥保护作用，运动因子对心血管靶细胞的作用机制涵盖糖脂代谢、动脉粥样硬化、内皮功能、心肌缺血和再灌注损伤、心肌收缩等方面。运动可引起各种运动因子的分泌，从而介导运动与心血管之间的联系，运动因子有可能成为CVD新的生物标志物，通过精准化的运动处方，在个性化运动干预中发挥作用。FGF21水平可作为一级预防的CVD风险生物标志物^[40]，较高水平的miR-21-5p、miR-122-5p和miR-320a-3p与心源性休克90 d病死率相关^[78]。循环miR-22-5p和miR-122-5p是诊断急性心肌梗死的有前景的新型生物标志物^[79]。相关研究也提供了新的治疗思路，有望通过外源性的运动因子来改善心血管健康，如重组FGF21给药可以防止2型糖尿病小鼠血脑屏障渗漏^[80]，但目前还只在动物试验阶段，需要更多的研究助其早日进入临床运用。目前对其中各种运动因子的发现及各因子发挥作用的机制仍处于初级阶段。运动如何促进运动因子的分泌也是一个未知的问题。运动和运动因子促进心血管的功能和机制值得展开更深入的研究，以指导临床运用。

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基金资助

国家重点研发计划重点专项(2022YFC2010201)

中央高校基本科研业务费专项资金资助(2024TNJN002)

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