运动调节自噬改善心血管疾病预后的研究进展

doi:10.12114/j.issn.1007-9572.2022.0524

摘要/Abstract

摘要： 心血管疾病是全球人类死亡的主要原因。自噬是一种高度保守的新陈代谢途径，其中溶酶体降解细胞器和大分子物质并循环利用，对心血管稳态和功能至关重要，但过度或不足的自噬可导致心血管疾病。越来越多的研究证明，运动是预防和改善心血管疾病预后的重要方法。运动调节自噬是双向和动态的过程。对于自噬过度或不足引起的心血管疾病，运动可恢复自噬水平及功能，延缓心血管疾病的进展，改善心室重构。本文综述了自噬的主要作用机制及信号通路，以及运动调节自噬有益于改善心血管疾病预后的作用，得出运动对心血管疾病自噬的调节机制有益于改善心血管疾病患者预后，降低心血管疾病事件发生率，但其改善心血管疾病预后的机制仍未充分阐述清楚，有待进一步研究。

关键词: 心血管疾病, 心肌梗死, 运动, 自噬, 综述

Abstract:

Cardiovascular disease is the leading cause of human mortality worldwide. Autophagy, a highly conserved metabolic pathway in which organelles and macromolecules are degraded by lysosomes and recycled, is essential for maintaining cardiovascular homeostasis and function, but excessive or insufficient autophagy could result in cardiovascular disease. A growing body of research has demonstrated that exercise is a critical component in preventing onset and improving the prognosis of cardiovascular disease. Exercise regulates autophagy bidirectional and dynamically. In cardiovascular disease caused by excessive or insufficient autophagy, exercise can restore autophagy level and function, delaying the progression of the disease, and improving ventricular remodeling. We reviewed the main mechanisms of autophagy and signaling pathways, as well as the beneficial effect of exercise-induced autophagy on prognosis of cardiovascular disease, and summarized that the mechanism of exercise regulating autophagy in cardiovascular diseases is beneficial to improving prognosis and reducing the incidence of cardiovascular events, but the mechanism for prognosis improvement is still not fully elaborated and needs further study.

Key words: Cardiovascular diseases, Myocardial infarction, Exercise, Autophagy, Review

吴长勇,保苏丽,徐菲,等. 运动调节自噬改善心血管疾病预后的研究进展[J]. 中国全科医学, 2023, 26(05): 629-634. DOI: 10.12114/j.issn.1007-9572.2022.0524.
WU Changyong,BAO Suli,XU Fei, et al. Latest Advances in Exercise-induced Autophagy in Improving Cardiovascular Disease Prognosis[J]. Chinese General Practice, 2023, 26(05): 629-634. DOI: 10.12114/j.issn.1007-9572.2022.0524.

图/表 2

图1 自噬过程概述及主要的信号通路机制注：AMP=一磷酸腺苷，ATP=三磷酸腺苷，AMPK=腺苷酸激活蛋白激酶，ATG、AMBRA1为自噬相关基因，Beclin1为自噬相关蛋白，BCL2=B细胞淋巴瘤2，FIP200=FAK家族激酶相互作用蛋白200 kDa，LC3=微管相关蛋白3，MTOR=哺乳动物雷帕霉素靶蛋白，P=磷酸，PI3P=3-磷酸磷脂酰肌醇，P62=自噬相关蛋白，ULK1=Unc-51如自噬激活激酶1，VPS15=夜泡蛋白分选15。在自噬过程中ULK1激酶复合物包括ATG13、ATG10、FIP200，PI3K复合物包括VPS34、ATG6/Beclin-1、ATG14和p150；LC3-Ⅱ和LC3-Ⅱ/LC3-Ⅰ比值可作为自噬含量及通量的标志物，LC3-Ⅱ升高标志自噬体含量增加从而诱导自噬，相反，LC3-Ⅱ减少可能是自噬通量增加导致其在溶酶体中被降解的结果；另外P62、Beclin1蛋白作也可作为自噬的标志物

Figure 1 Overview of the autophagic process and main signaling pathway mechanisms

图2 运动诱导自噬的分子递质有益于心血管疾病注：FOXO=叉头转录因子；运动通过FOXO和TEEB调控ATG家族的转录增加自噬能力，其中FOXO是通过AKT/AMPK介导调节运动应答中自噬成分的转录，包括LC3和BNIP3等。AMPK和MTOR分别是运动诱导自噬的激活因子和抑制因子，与ROS共同调节自噬通量，且AMPK可抑制MTOR。运动诱导自噬的有益作用包括降解受损的蛋白质和细胞器、提高线粒体氧化能力，降低心肌细胞凋亡，减少炎性反应及心肌纤维化形成，改善心脏纤维化及心功能

Figure 2 Molecular mediators used in the inducing of autophagy by exercise are beneficial to cardiovascular disease improvement

参考文献 55

[1]	VIRANI S S，ALONSO A，BENJAMIN E J，et al. Heart disease and stroke statistics-2020 update：a report from the American heart association[J]. Circulation，2020，141（9）：e139-596. DOI：10.1161/CIR.0000000000000757.
[2]	中国心血管健康与疾病报告编写组. 中国心血管健康与疾病报告2020概要[J]. 中国循环杂志，2021，36（6）：521-545. DOI：10.3969/j.issn.1000-3614.2021.06.001.
[3]	KROEMER G，LEVINE B. Autophagic cell death：the story of a misnomer[J]. Nat Rev Mol Cell Biol，2008，9（12）：1004-1010. DOI：10.1038/nrm2529.
[4]	GALLUZZI L，GREEN D R. Autophagy-independent functions of the autophagy machinery[J]. Cell，2019，177（7）：1682-1699. DOI：10.1016/j.cell.2019.05.026.
[5]	THOMAS R J，BEATTY A L，BECKIE T M，et al. Home-based cardiac rehabilitation：a scientific statement from the American association of cardiovascular and pulmonary rehabilitation，the American Heart Association，and the American College of Cardiology[J]. J Am Coll Cardiol，2019，74（1）：133-153. DOI：10.1016/j.jacc.2019.03.008.
[6]	中国心血管疾病患者居家康复专家共识编写组. 中国心血管疾病患者居家康复专家共识[J]. 中国循环杂志，2022，37（2）：108-121. DOI：10.3969/j.issn.1000-3614.2022.02.002.
[7]	PELLICCIA A，SHARMA S，GATI S，et al. 2020 ESC Guidelines on sports cardiology and exercise in patients with cardiovascular disease[J]. Eur Heart J，2021，42（1）：17-96. DOI：10.1093/eurheartj/ehaa605.
[8]	VEGA R B，KONHILAS J P，KELLY D P，et al. Molecular mechanisms underlying cardiac adaptation to exercise[J]. Cell Metab，2017，25（5）：1012-1026. DOI：10.1016/j.cmet.2017.04.025.
[9]	BERNARDO B C，OOI J Y Y，WEEKS K L，et al. Understanding key mechanisms of exercise-induced cardiac protection to mitigate disease：current knowledge and emerging concepts[J]. Physiol Rev，2018，98（1）：419-475. DOI：10.1152/physrev.00043.2016.
[10]	DOIMO S，FABRIS E，PIEPOLI M，et al. Impact of ambulatory cardiac rehabilitation on cardiovascular outcomes：a long-term follow-up study[J]. Eur Heart J，2019，40（8）：678-685. DOI：10.1093/eurheartj/ehy417.
[11]	LI H Z，QIN S G，LIANG Q Q，et al. Exercise training enhances myocardial mitophagy and improves cardiac function via Iris in/ FNDC5-PINK1/parkin pathway in MI mice[J]. Biomedicines，2021，9（6）：701. DOI：10.3390/biomedicines9060701.
[12]	SANCHIS-GOMAR F，LAVIE C J，MARíN J，et al. Exercise effects on cardiovascular disease：from basic aspects to clinical evidence[J]. Cardiovasc Res，2022，118（10）：2253-2266. DOI：10.1093/cvr/cvab272.
[13]	CLARK S L Jr. Cellular differentiation in the kidneys of newborn mice studies with the electron microscope[J]. J Biophys Biochem Cytol，1957，3（3）：349-362. DOI：10.1083/jcb.3.3.349.
[14]	KLIONSKY D J，ABDEL-AZIZ A K，ABDELFATAH S，et al. Guidelines for the use and interpretation of assays for monitoring autophagy （4th edition）¹[J]. Autophagy，2021，17（1）：1-382. DOI：10.1080/15548627.2020.1797280.
[15]	COSTA R，MORRISON A，WANG J，et al. Activated protein C modulates cardiac metabolism and augments autophagy in the ischemic heart[J]. J Thromb Haemost，2012，10（9）：1736-1744. DOI：10.1111/j.1538-7836.2012.04833.x.
[16]	TIAN W S，ALSAADI R，GUO Z H，et al. An antibody for analysis of autophagy induction[J]. Nat Methods，2020，17（2）：232-239. DOI：10.1038/s41592-019-0661-y.
[17]	DU J，ZHANG C C，ZHAO W. Autophagy and hypertension[J]. Adv Exp Med Biol，2020，1207：213-216. DOI：10.1007/978-981-15-4272-5_14.
[18]	HONG G L，RUI G，ZHANG D D，et al. A smartphone-assisted pressure-measuring-based diagnosis system for acute myocardial infarction diagnosis[J]. Int J Nanomedicine，2019，14：2451-2464. DOI：10.2147/IJN.S197541.
[19]	CORSETTI G，CHEN-SCARABELLI C，ROMANO C，et al. Autophagy and oncosis/necroptosis are enhanced in cardiomyocytes from heart failure patients[J]. Med Sci Monit Basic Res，2019，25：33-44. DOI：10.12659/MSMBR.913436.
[20]	ZHENG D D，HUO M，LI B，et al. The role of exosomes and exosomal microRNA in cardiovascular disease[J]. Front Cell Dev Biol，2020，8：616161. DOI：10.3389/fcell.2020.616161.
[21]	YUAN Z，HUANG W Q. New developments in exosomal lncRNAs in cardiovascular diseases[J]. Front Cardiovasc Med，2021，8：709169. DOI：10.3389/fcvm.2021.709169.
[22]	JUSIC A，THOMAS P B，WETTINGER S B，et al. Noncoding RNAs in age-related cardiovascular diseases[J]. Ageing Res Rev，2022，77：101610. DOI：10.1016/j.arr.2022.101610.
[23]	ZHU L W，LI N，SUN L B，et al. Non-coding RNAs：the key detectors and regulators in cardiovascular disease[J]. Genomics，2021，113（1 Pt 2）：1233-1246. DOI：10.1016/j.ygeno.2020.10.024.
[24]	CHEN C，YANG S L，LI H P，et al. Mir30c is involved in diabetic cardiomyopathy through regulation of cardiac autophagy via BECN1[J]. Mol Ther Nucleic Acids，2017，7：127-139. DOI：10.1016/j.omtn.2017.03.005.
[25]	FENG Y，XU W T，ZHANG W，et al. LncRNA DCRF regulates cardiomyocyte autophagy by targeting miR-551b-5p in diabetic cardiomyopathy[J]. Theranostics，2019，9（15）：4558-4566. DOI：10.7150/thno.31052.
[26]	SHI J Y，CHEN C，XU X，et al. miR-29a promotes pathological cardiac hypertrophy by targeting the PTEN/AKT/mTOR signalling pathway and suppressing autophagy[J]. Acta Physiol （Oxf），2019，227（2）：e13323. DOI：10.1111/apha.13323.
[27]	JIN L H，ZHOU Y，HAN L Z，et al. microRNA302-367-PI3K-PTEN-AKT-mTORC1 pathway promotes the development of cardiac hypertrophy through controlling autophagy[J]. In Vitro Cell Dev Biol Anim，2020，56（2）：112-119. DOI：10.1007/s11626-019-00417-5.
[28]	LIANG H H，SU X M，WU Q X，et al. LncRNA 2810403D21Rik/Mirf promotes ischemic myocardial injury by regulating autophagy through targeting mir26a[J]. Autophagy，2020，16（6）：1077-1091. DOI：10.1080/15548627.2019.1659610.
[29]	LIU C Y，ZHANG Y H，LI R B，et al. LncRNA CAIF inhibits autophagy and attenuates myocardial infarction by blocking p53-mediated myocardin transcription[J]. Nat Commun，2018，9（1）：29. DOI：10.1038/s41467-017-02280-y.
[30]	ZHANG B F，JIANG H，CHEN J，et al. LncRNA H19 ameliorates myocardial infarction-induced myocardial injury and maladaptive cardiac remodelling by regulating KDM3A[J]. J Cell Mol Med，2020，24（1）：1099-1115. DOI：10.1111/jcmm.14846.
[31]	LEE Y，KANG E B，KWON I，et al. Cardiac kinetophagy coincides with activation of anabolic signaling[J]. Med Sci Sports Exerc，2016，48（2）：219-226. DOI：10.1249/MSS.0000000000000774.
[32]	CHEN C Y，HSU H C，LEE B C，et al. Exercise training improves cardiac function in infarcted rabbits：involvement of autophagic function and fatty acid utilization[J]. Eur J Heart Fail，2010，12（4）：323-330. DOI：10.1093/eurjhf/hfq028.
[33]	KOMATSU M，WAGURI S，UENO T，et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice[J]. J Cell Biol，2005，169（3）：425-434. DOI：10.1083/jcb.200412022.
[34]	HAZARI Y，BRAVO-SAN PEDRO J M，HETZ C，et al. Autophagy in hepatic adaptation to stress[J]. J Hepatol，2020，72（1）：183-196. DOI：10.1016/j.jhep.2019.08.026.
[35]	NICHENKO A S，SORENSEN J R，SOUTHERN W M，et al. Lifelong Ulk1-mediated autophagy deficiency in muscle induces mitochondrial dysfunction and contractile weakness[J]. Int J Mol Sci，2021，22（4）：1937. DOI：10.3390/ijms22041937.
[36]	FERNANDES S A，ALMEIDA C F，SOUZA L S，et al. Altered in vitro muscle differentiation in X-linked myopathy with excessive autophagy[J]. Dis Model Mech，2020，13（2）：dmm041244. DOI：10.1242/dmm.041244.
[37]	ALON T，SADEH M，LEV D，et al. X-linked myopathy with excessive autophagy：first report of an Israeli family presenting with late onset lower limb girdle weakness[J]. Neuromuscul Disord，2021，31（9）：854-858. DOI：10.1016/j.nmd.2021.06.013.
[38]	LIAO Z F，LI D，CHEN Y L，et al. Early moderate exercise benefits myocardial infarction healing via improvement of inflammation and ventricular remodelling in rats[J]. J Cell Mol Med，2019，23（12）：8328-8342. DOI：10.1111/jcmm.14710.
[39]	WILLIS M S，MIN J N，WANG S B，et al. Carboxyl Terminus of Hsp70-interacting protein （CHIP） is required to modulate cardiac hypertrophy and attenuate autophagy during exercise[J]. Cell Biochem Funct，2013，31（8）：724-735. DOI：10.1002/cbf.2962.
[40]	CAMPOS J C，QUELICONI B B，BOZI L H M，et al. Exercise reestablishes autophagic flux and mitochondrial quality control in heart failure[J]. Autophagy，2017，13（8）：1304-1317. DOI：10.1080/15548627.2017.1325062.
[41]	TAO L C，BEI Y H，LIN S H，et al. Exercise training protects against acute myocardial infarction via improving myocardial energy metabolism and mitochondrial biogenesis[J]. Cell Physiol Biochem，2015，37（1）：162-175. DOI：10.1159/000430342.
[42]	LIANG Q Q，CAI M X，ZHANG J Q，et al. Role of muscle-specific histone methyltransferase （Smyd1） in exercise-induced cardioprotection against pathological remodeling after myocardial infarction[J]. Int J Mol Sci，2020，21（19）：E7010. DOI：10.3390/ijms21197010.
[43]	BATISTA D F，POLEGATO B F，DA SILVA R C，et al. Impact of modality and intensity of early exercise training on ventricular remodeling after myocardial infarction[J]. Oxid Med Cell Longev，2020，2020：5041791. DOI：10.1155/2020/5041791.
[44]	JIA D D，HOU L，LV Y Z，et al. Postinfarction exercise training alleviates cardiac dysfunction and adverse remodeling via mitochondrial biogenesis and SIRT1/PGC-1α/PI3K/Akt signaling[J]. J Cell Physiol，2019，234（12）：23705-23718. DOI：10.1002/jcp.28939.
[45]	SONG W，LIANG Q Q，CAI M X，et al. HIF-1α-induced up-regulation of microRNA-126 contributes to the effectiveness of exercise training on myocardial angiogenesis in myocardial infarction rats[J]. J Cell Mol Med，2020，24（22）：12970-12979. DOI：10.1111/jcmm.15892.
[46]	GUO C，CHEN M J，ZHAO J R，et al. Exercise training improves cardiac function and regulates myocardial mitophagy differently in ischaemic and pressure-overload heart failure mice[J]. Exp Physiol，2022，107（6）：562-574. DOI：10.1113/EP090374.
[47]	ANKER S D，COATS A J S. Exercise for frail，elderly patients with acute heart failure - a strong step forward[J]. N Engl J Med，2021，385（3）：276-277. DOI：10.1056/NEJMe2106140.
[48]	BOZKURT B，FONAROW G C，GOLDBERG L R，et al. Cardiac rehabilitation for patients with heart failure：JACC expert panel[J]. J Am Coll Cardiol，2021，77（11）：1454-1469. DOI：10.1016/j.jacc.2021.01.030.
[49]	XI Y，HAO M L，LIANG Q Q，et al. Dynamic resistance exercise increases skeletal muscle-derived FSTL1 inducing cardiac angiogenesis via DIP2A-Smad2/3 in rats following myocardial infarction[J]. J Sport Health Sci，2021，10（5）：594-603. DOI：10.1016/j.jshs.2020.11.010.
[50]	TAM B T，PEI X M，YUNG B Y，et al. Autophagic adaptations to long-term habitual exercise in cardiac muscle[J]. Int J Sports Med，2015，36（7）：526-534. DOI：10.1055/s-0034-1398494.
[51]	MEJíAS-PEÑA Y，RODRIGUEZ-MIGUELEZ P，FERNANDEZ-GONZALO R，et al. Effects of aerobic training on markers of autophagy in the elderly[J]. Age （Dordr），2016，38（2）：33. DOI：10.1007/s11357-016-9897-y.
[52]	AAS S N，TØMMERBAKKE D，GODAGER S，et al. Effects of acute and chronic strength training on skeletal muscle autophagy in frail elderly men and women[J]. Exp Gerontol，2020，142：111122. DOI：10.1016/j.exger.2020.111122.
[53]	HENTILÄ J，AHTIAINEN J P，PAULSEN G，et al. Autophagy is induced by resistance exercise in young men，but unfolded protein response is induced regardless of age[J]. Acta Physiol （Oxf），2018，224（1）：e13069. DOI：10.1111/apha.13069.
[54]	MOREIRA J B N，WOHLWEND M，WISLØFF U. Exercise and cardiac health：physiological and molecular insights[J]. Nat Metab，2020，2（9）：829-839. DOI：10.1038/s42255-020-0262-1.
[55]	SEO D Y，KWAK H B，KIM A H，et al. Cardiac adaptation to exercise training in health and disease[J]. Pflugers Arch，2020，472（2）：155-168. DOI：10.1007/s00424-019-02266-3.