冉玉柳,谭玉燕,刘 燕

心肌梗死后心肌纤维化引发的心血管疾病（Cardiovascular diseases，CVDs）是全球范围内引起健康损失的主要原因之一，是一种复杂的综合征。其机制复杂多样，由多因素相互作用、共同参与所致。其中机制较为明确，并且在心肌纤维化进程中扮演重要作用的是PI3K/AKT/mTOR自噬通路。心肌梗死后可通过抑制PI3K-AKT-mTOR信号通路持续发挥生物学效应诱导自噬，从而减轻心肌梗死后心肌纤维化。因此，明确如何控制PI3K/AKT/mTOR自噬通路是治疗心肌梗死后心肌纤维化的重要研究方向，本文就目前基于PI3K/AKT/mTOR自噬通路在治疗心肌梗死后心肌纤维化的研究进行综述。

心肌梗死；心肌纤维化；PI3K-AKT-mTOR通路；自噬；治疗进展

[1] Tang X,Zhu Y,Guan W,et al.Advances in nanosensors for cardiovascular disease detection[J].Life Sci,2022,305:120733. [2] Zhao D,Liu J,Wang M,et al.Epidemiology of cardiovascular disease in China:current features and implications[J].Nat Rev Cardiol, 2019,16(4):203-212. [3] 刘明波,何新叶,杨晓红,等.《中国心血管健康与疾病报告2023》要点解读[J].中国心血管杂志,2024,29(04):305-324. [4] Ikeda S,Zablocki D,Sadoshima J.The role of autophagy in death of cardiomyocytes[J].J Mol Cell Cardiol,2022,165:1-8. [5] Chen E,Chen C,Niu Z,et al.Poly(I:C)preconditioning protects the heart against myocardial ischemia/reperfusion injury through TLR3/PI3K/Akt-dependent pathway[J].Signal Transduct Target Ther,2020,5(1):216. [6] Tallquist M D.Cardiac Fibroblast Diversity[J].Annu Rev Physiol,2020,82:63-78. [7] Ambale-Venkatesh B,Lima J A.Cardiac MRI:a central prognostic tool in myocardial fibrosis[J].Nat Rev Cardiol,2015,12(1):18-29. [8] Jellis C L,Kwon D H.Myocardial T1 mapping:modalities and clinical applications[J].Cardiovasc Diagn Ther,2014,4(2):126-137. [9] Porter K E,Turner N A.Cardiac fibroblasts:at the heart of myocardial remodeling[J].Pharmacol Ther,2009,123(2):255-278. [10] AlQudah M,Hale T M,Czubryt M P.Targeting the renin-angiotensin-aldosterone system in fibrosis[J].Matrix Biol,2020,91-92:92-108. [11] Mizushima N,Levine B.Autophagy in Human Diseases[J].N Engl J Med,2020,383(16):1564-1576. [12] Lu C,Yang Y,Zhu Y,et al.An Intervention Target for Myocardial Fibrosis:Autophagy[J].Biomed Res Int,2018,2018:6215916. [13] Shirakabe A,Ikeda Y,Sciarretta S,et al.Aging and Autophagy in the Heart[J].Circ Res,2016,118(10):1563-1576. [14] Gatica D,Chiong M,Lavandero S,et al.Molecular mechanisms of autophagy in the cardiovascular system[J].Circ Res,2015,116(3):456-467. [15] Yao Q,Ke Z Q,Guo S,et al.Curcumin protects against diabetic cardiomyopathy by promoting autophagy and alleviating apoptosis[J].J Mol Cell Cardiol,2018,124:26-34. [16] Bilanges B,Posor Y,Vanhaesebroeck B.PI3K isoforms in cell signalling and vesicle trafficking[J].Nat Rev Mol Cell Biol,2019,20(9):515-534. [17] Osorio-Fuentealba C,Klip A.Dissecting signalling by individual Akt/PKB isoforms,three steps at once[J].Biochem J,2015,470(2):e13-e16. [18] Tan P,Wang Y J,Li S,et al.The PI3K/Akt/mTOR pathway regulates the replicative senescence of human VSMCs[J].Mol Cell Biochem, 2016,422(1-2):1-10. [19] Xu Z,Han X,Ou D,et al.Targeting PI3K/AKT/mTOR-mediated autophagy for tumor therapy[J].Appl Microbiol Biotechnol,2020, 104(2):575-587. [20] Dunlop E A,Tee A R.The kinase triad,AMPK,mTORC1 and ULK1,maintains energy and nutrient homoeostasis[J].Biochem Soc Trans, 2013,41(4):939-943. [21] Papinski D,Kraft C.Regulation of Autophagy By Signaling Through the Atg1/ULK1 Complex[J].J Mol Biol,2016,428(9 Pt A):1725-1741. [22] Lv X,Zhu Y,Deng Y,et al.Glycyrrhizin improved autophagy flux via HMGB1-dependent Akt/mTOR signaling pathway to prevent Doxorubicin-induced cardiotoxicity[J].Toxicology,2020,441:152508. [23] Yu Y,Hu Z,Li B,et al.Ivabradine improved left ventricular function and pressure overload-induced cardiomyocyte apoptosis in a transverse aortic constriction mouse model[J].Mol Cell Biochem,2019,450(1-2):25-34. [24] Zhang P,Liu X,Yu X,et al.Protective Effects of Liriodendrin on Myocardial Infarction-Induced Fibrosis in Rats via the PI3K/Akt Autophagy Pathway:A Network Pharmacology Study[J].Comb Chem High Throughput Screen,2024,27(11):1566-1575. [25] Li N,Xia N,He J,et al.Amphiregulin improves ventricular remodeling after myocardial infarction by modulating autophagy and apoptosis[J].FASEB J,2024,38(4):e23488. [26] Gong H,Lyu X,Wang Q,et al.Endothelial to mesenchymal transition in the cardiovascular system[J].Life Sci,2017,184:95-102. [27] Ke X,Chen X,Yan L,et al.Vaspin contributes to autophagy and endothelial-to-mesenchymal transition via PI3K-/AKT-mTOR pathway[J].Acta Histochem,2022,124(4):151881. [28] Lv S,Yuan P,Lu C,et al.QiShenYiQi pill activates autophagy to attenuate reactive myocardial fibrosis via the PI3K/AKT/mTOR pathway[J].Aging(Albany NY),2021,13(4):5525-5538. [29] Xue Y,Zhang M,Liu M,et al.8-Gingerol Ameliorates Myocardial Fibrosis by Attenuating Reactive Oxygen Species,Apoptosis,and Autophagy via the PI3K/Akt/mTOR Signaling Pathway[J].Front Pharmacol,2021,12:711701. [30] Li Q,Dong Q T,Yang Y J,et al.AMPK-mediated cardioprotection of atorvastatin relates to the reduction of apoptosis and activation of autophagy in infarcted rat hearts[J].Am J Transl Res,2016,8(10):4160-4171. [31] 陆海英,周娟,陆敏,等.丹参酚酸B对实验性肾间质纤维化大鼠的保护作用及其机制[J].中药材,2010,33(11):1755-1759. [32] 吴航.丹参酚酸B通过Sirt-1对大鼠肝纤维化模型的影响[J].华北理工大学学报(医学版),2016,18(05):349-352. [33] 金粟,李士远,陈芳宁,等.丹酚酸B､甘草次酸､白藜芦醇单用及联用对小鼠肺间质纤维化影响的实验研究[J].中华中医药学刊, 2016,34(05):1095-1098. [34] 杜琎,石开虎,赵扬,等.丹参酚酸B通过抑制PI3K/AKT/mTOR通路促进自噬减轻大鼠心肌纤维化的研究[J].现代生物医学进展,2019,19(20):3812-3817. [35] Lv S,Yuan P,Lu C,et al.QiShenYiQi pill activates autophagy to attenuate reactive myocardial fibrosis via the PI3K/AKT/mTOR pathway[J].Aging(Albany NY),2021,13(4):5525-5538. [36] 郑艳,刘艳辉,胡杰,等.犀草素对心力衰竭大鼠心室重构的改善和对PI3K/Akt/mTOR信号通路的调控作用[J].中国心血管杂志,2021,26(02):169-173. [37] 赵研,甘芮溪,张小月,等.二参真武汤调控PI3K/AKT/mTOR信号通路抑制心肌纤维化的体外实验研究[J].安徽中医药大学学报,2023,42(03):77-82. [38] Li J J,Liu Y,Zhao J,et al.[Transplantation of cardiac stem cells overexpressing integrin-linked kinase improves cardiac function in a rat model of acute myocardial infarction][J].Zhonghua Xin Xue Guan Bing Za Zhi,2017,45(10):880-886. [39] Puddighinu G,D'Amario D,Foglio E,et al.Molecular mechanisms of cardioprotective effects mediated by transplanted cardiac ckit(+)cells through the activation of an inflammatory hypoxia-dependent reparative response[J].Oncotarget,2018,9(1):937-957. [40] Kompa A R,Greening D W,Kong A M,et al.Sustained subcutaneous delivery of secretome of human cardiac stem cells promotes cardiac repair following myocardial infarction[J].Cardiovasc Res,2021,117(3):918-929. [41] Picchio V,Pagano F,Carnevale R,et al.Exposure to serum from exclusive heated tobacco product smokers induces mTOR activation and fibrotic features in human cardiac stromal cells[J].Biochim Biophys Acta Mol Basis Dis,2024,1870(7):167350. [42] Wang S,Li L,Liu T,et al.miR-19a/19b-loaded exosomes in combination with mesenchymal stem cell transplantation in a preclinical model of myocardial infarction[J].Regen Med,2020,15(6):1749-1759. [43] Wang X,Liu Y,Hou H,et al.miRNA-29 aggravates myocardial infarction via inhibiting the PI3K/mTOR/HIF1alpha/VEGF pathway[J].Aging(Albany NY),2022,14(7):3129-3142. [44] Wu C,Bao S,Li R,et al.Noncoding RNAs and Cardiac Fibrosis[J].Rev Cardiovasc Med,2023,24(2):63. [45] Yuan J,Yang H,Liu C,et al.Microneedle Patch Loaded with Exosomes Containing MicroRNA-29b Prevents Cardiac Fibrosis after Myocardial Infarction[J].Adv Healthc Mater,2023,12(13):e2202959. [46] Peng C,Yan J,Jiang Y,et al.Exploring Cutting-Edge Approaches to Potentiate Mesenchymal Stem Cell and Exosome Therapy for Myocardial Infarction[J].J Cardiovasc Transl Res,2024,17(2):356-375. [47] Gu J,Chen X,Luo Z,et al.Cardiomyocyte-derived exosomes promote cardiomyocyte proliferation and neonatal heart regeneration[J]. FASEB J,2024,38(22):e70186.

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