
浏览全部资源
扫码关注微信
1.内蒙古科技大学包头医学院,包头 014000
2.内蒙古科技大学包头医学院第一附属医院心功能科,包头 014000
3.内蒙古科技大学包头医学院第一附属医院中心实验室,包头 014000
齐婷婷,Email:qitingtingtt@126.com,研究方向:心血管病基础与临床。
张 昕,Email:zhangxinwdq@sina.com。
收稿:2025-03-09,
修回:2025-05-11,
录用:2025-06-04,
纸质出版:2025-11-28
移动端阅览
齐婷婷,张昕,白力等.程序性细胞死亡在心肌纤维化中的研究进展[J].重庆医科大学学报,2025,50(11):1601-1608.
Qi Tingting,Zhang Xin,Bai Li,et al.Research advances in programmed cell death mechanisms underlying myocardial fibrosis[J].Journal of Chongqing Medical University,2025,50(11):1601-1608.
齐婷婷,张昕,白力等.程序性细胞死亡在心肌纤维化中的研究进展[J].重庆医科大学学报,2025,50(11):1601-1608. DOI: 10.13406/j.cnki.cyxb.003904.
Qi Tingting,Zhang Xin,Bai Li,et al.Research advances in programmed cell death mechanisms underlying myocardial fibrosis[J].Journal of Chongqing Medical University,2025,50(11):1601-1608. DOI: 10.13406/j.cnki.cyxb.003904.
心肌纤维化(myocardial fibrosis,MF)的发生和发展受多种细胞因子和信号通路的影响。近年来研究显示,MF的进展与程序性细胞死亡(programmed cell death,PCD)之间有着极为紧密的关联,如凋亡、自噬、焦亡、坏死、铁死亡、铜死亡。本文对MF以及各类程序性细胞死亡的特性展开综述,着重阐述PCD在MF研究领域的最新进展情况,期望能够为MF的深入探究以及临床干预提供理论层面的参考依据。
The pathogenesis and progression of myocardial fibrosis(MF) are modulated by diverse cytokines and signaling pathways. Studies in recent years have revealed an extremely close association between MF evolution and programmed cell death(PCD) modalities,including apoptosis,autophagy,pyroptosis,necrosis,ferroptosis,and cuproptosis. This article reviews the characteristics of MF and distinct PCD modalities,with particular emphasis on cutting-edge discoveries elucidating PCD in the field of MF,hoping to provide a theoretical-level reference basis for the in-depth exploration and clinical intervention of MF.
Frangogiannis NG . Cardiac fibrosis [J ] . Cardiovasc Res , 2021 , 117 ( 6 ): 1450 - 1488 .
Frangogiannis NG . The extracellular matrix in ischemic and nonischemic heart failure [J ] . Circ Res , 2019 , 125 ( 1 ): 117 - 146 .
de Boer RA , De Keulenaer G , Bauersachs J , et al . Towards better definition,quantification and treatment of fibrosis in heart failure. A scientific roadmap by the Committee of Translational Research of the Heart Failure Association(HFA) of the European Society of Cardiology [J ] . Eur J Heart Fail , 2019 , 21 ( 3 ): 272 - 285 .
Liu T , Song D , Dong J , et al . Current understanding of the pathophysiology of myocardial fibrosis and its quantitative assessment in heart failure [J ] . Front Physiol , 2017 , 8 : 238 .
Garg P , Assadi H , Jones R , et al . Left ventricular fibrosis and hypertrophy are associated with mortality in heart failure with preserved ejection fraction [J ] . Sci Rep , 2021 , 11 ( 1 ): 617 .
Lewis GA , Dodd S , Clayton D , et al . Pirfenidone in heart failure with preserved ejection fraction:a randomized phase 2 trial [J ] . Nat Med , 2021 , 27 ( 8 ): 1477 - 1482 .
Sweeney M , Corden B , Cook SA . Targeting cardiac fibrosis in heart failure with preserved ejection fraction:mirage or miracle? [J ] . EMBO Mol Med , 2020 , 12 ( 10 ): e10865 .
Nagaraju CK , Dries E , Popovic N , et al . Global fibroblast activation throughout the left ventricle but localized fibrosis after myocardial infarction [J ] . Sci Rep , 2017 , 7 ( 1 ): 10801 .
Prabhu SD , Frangogiannis NG . The biological basis for cardiac repair after myocardial infarction:from inflammation to fibrosis [J ] . Circ Res , 2016 , 119 ( 1 ): 91 - 112 .
Zeng KF , Wang HJ , Deng B , et al . Ethyl ferulate suppresses post-myocardial infarction myocardial fibrosis by inhibiting transforming growth factor receptor 1 [J ] . Phytomedicine , 2023 , 121 : 155118 .
Cavarretta E , Condorelli G . miR-21 and cardiac fibrosis:another brick in the wall? [J ] . Eur Heart J , 2015 , 36 ( 32 ): 2139 - 2141 .
Nagpal V , Rai R , Place AT , et al . MiR-125b is critical for fibroblast-to-myofibroblast transition and cardiac fibrosis [J ] . Circulation , 2016 , 133 ( 3 ): 291 - 301 .
Zhou XL , Xu H , Liu ZB , et al . miR-21 promotes cardiac fibroblast-to-myofibroblast transformation and myocardial fibrosis by targeting Jagged1 [J ] . J Cell Mol Med , 2018 , 22 ( 8 ): 3816 - 3824 .
Wei X , Lv Y , Yang C , et al . Bufalin reduces myocardial infarction-induced myocardial fibrosis and improves cardiac function by inhibiting the NLRP3/IL-1β signalling pathway [J ] . Clin Exp Pharmacol Physiol , 2023 , 50 ( 8 ): 688 - 697 .
Hu Y , Peng XP . Single-cell sequencing reveals LRRc17-mediated modulation of cardiac fibroblast ferroptosis in regulating myocardial fibrosis after myocardial infarction [J ] . Cell Signal , 2024 , 121 : 111293 .
Anonymous . Guideline for the pharmacological treatment of hypertension in adults [M ] . Geneva : World Health Organization , 2021 .
González A , Schelbert EB , Díez J , et al . Myocardial interstitial fibrosis in heart failure biological and translational perspectives [J ] . J Am Coll Cardiol , 2018 , 71 ( 15 ): 1696 - 1706 .
Raman B , Ariga R , Spartera M , et al . Progression of myocardial fibrosis in hypertrophic cardiomyopathy:mechanisms and clinical implications [J ] . Eur Heart J Cardiovasc Imaging , 2019 , 20 ( 2 ): 157 - 167 .
Park S , Nguyen NB , Pezhouman A , et al . Cardiac fibrosis:potential therapeutic targets [J ] . Transl Res , 2019 , 209 : 121 - 137 .
Kang SC , Sohn EH , Lee SR . Hydrogen sulfide as a potential alternative for the treatment of myocardial fibrosis [J ] . Oxid Med Cell Longev , 2020 , 2020 : 4105382 .
Pitt B , Diez J . Possible role of gut microbiota alterations in myocardial fibrosis and burden of heart failure in hypertensive heart disease [J ] . Hypertension , 2024 , 81 ( 7 ): 1467 - 1476 .
Sun H , Saeedi P , Karuranga S , et al . IDF Diabetes Atlas:Global,regional and country-level diabetes prevalence estimates for 2021 and projections for 2045 [J ] . Diabetes Res Clin Pract , 2022 , 183 : 109119 .
Salvador DB , Gamba MR , Gonzalez-Jaramillo N , et al . Diabetes and myocardial fibrosis A systematic review and meta-analysis [J ] . JACC Cardiovasc Imag , 2022 , 15 ( 5 ): 796 - 808 .
Fowlkes V , Clark J , Fix C , et al . Type II diabetes promotes a myofibroblast phenotype in cardiac fibroblasts [J ] . Life Sci , 2013 , 92 ( 11 ): 669 - 676 .
Kota SK , Kota SK , Jammula S , et al . Effect of diabetes on alteration of metabolism in cardiac myocytes:therapeutic implications [J ] . Diabetes Technol Ther , 2011 , 13 ( 11 ): 1155 - 1160 .
Li CG , Zhang J , Xue M , et al . SGLT2 inhibition with empagliflozin attenuates myocardial oxidative stress and fibrosis in diabetic mice heart [J ] . Cardiovasc Diabetol , 2019 , 18 ( 1 ): 15 .
Wang S , Du Y , Zhang B , et al . Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient [J ] . Cell , 2024 , 187 ( 22 ): 6152 - 6164 .
Nattel S . How does fibrosis promote atrial fibrillation persistence:in silico findings,clinical observations,and experimental data [J ] . Cardiovasc Res , 2016 , 110 ( 3 ): 295 - 297 .
Slawik J , Adrian L , Hohl M , et al . Irregular pacing of ventricular cardiomyocytes induces pro-fibrotic signalling involving paracrine effects of transforming growth factor beta and connective tissue growth factor [J ] . Eur J Heart Fail , 2019 , 21 ( 4 ): 482 - 491 .
Zhu L , Wang Y , Zhao S , et al . Detection of myocardial fibrosis:where we stand [J ] . Front Cardiovasc Med , 2022 , 9 : 926378 .
Schiau C , Leucuța DC , Dudea SM , et al . Myocardial fibrosis as a predictor of ventricular arrhythmias in patients with non-ischemic cardiomyopathy [J ] . In Vivo , 2021 , 35 ( 3 ): 1677 - 1685 .
Elmore S . Apoptosis:a review of programmed cell death [J ] . Toxicol Pathol , 2007 , 35 ( 4 ): 495 - 516 .
D’Arcy MS . Cell death:a review of the major forms of apoptosis,necrosis and autophagy [J ] . Cell Biol Int , 2019 , 43 ( 6 ): 582 - 592 .
Lockshin RA . Programmed cell death 50(and beyond) [J ] . Cell Death Differ , 2016 , 23 ( 1 ): 10 - 17 .
Kawaguchi M , Takahashi M , Hata T , et al . Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury [J ] . Circulation , 2011 , 123 ( 6 ): 594 - 604 .
Kerr JF , Wyllie AH , Currie AR . Apoptosis:a basic biological phenomenon with wide-ranging implications in tissue kinetics [J ] . Br J Cancer , 1972 , 26 ( 4 ): 239 - 257 .
Kalkavan H , Green DR . MOMP,cell suicide as a BCL-2 family business [J ] . Cell Death Differ , 2018 , 25 ( 1 ): 46 - 55 .
Xiong SB , Mu TY , Wang GW , et al . Mitochondria-mediated apoptosis in mammals [J ] . Protein Cell , 2014 , 5 ( 10 ): 737 - 749 .
Ashkenazi A . Targeting the extrinsic apoptotic pathway in cancer:lessons learned and future directions [J ] . J Clin Invest , 2015 , 125 ( 2 ): 487 - 489 .
Verbrugge I , Johnstone RW , Smyth MJ . SnapShot:extrinsic apoptosis pathways [J ] . Cell , 2010 , 143 ( 7 ): 1192 - 1192 .
Wang Y , Ouyang M , Wang Q , et al . MicroRNA-142-3p inhibits hypoxia/reoxygenation-induced apoptosis and fibrosis of cardiomyocytes by targeting high mobility group box 1 [J ] . Int J Mol Med , 2016 , 38 ( 5 ): 1377 - 1386 .
Hao M , Jiao K . Jatrorrhizine reduces myocardial infarction-induced apoptosis and fibrosis through inhibiting p53 and TGF-β1/Smad2/3 pathways in mice [J ] . Acta Cir Bras , 2022 , 37 ( 7 ): e370705 .
Song WF , Chen Z , Zhang M , et al . Bilobalide prevents apoptosis andImproves cardiac function in myocardial infarction [J ] . Mol Biotechnol , 2024 , 66 ( 3 ): 442 - 453 .
Liu ZY , You QY , Liu ZY , et al . m6A control programmed cell death in cardiac fibrosis [J ] . Life Sci , 2024 , 353 : 122922 .
de Duve C . The lysosome [J ] . Sci Am , 1963 , 208 ( 5 ): 64 - 73 .
Ahn HH , Oh Y , Lee H , et al . Identification of glucose-6-phosphate transporter as a key regulator functioning at the autophagy initiation step [J ] . FEBS Lett , 2015 , 589 ( 16 ): 2100 - 2109 .
Lystad AH , Carlsson SR , Simonsen A . Toward the function of mammalian ATG12-ATG5-ATG16L1 complex in autophagy and related processes [J ] . Autophagy , 2019 , 15 ( 8 ): 1485 - 1486 .
Song X , Nie L , Long J , et al . Hydrogen sulfide alleviates hypothyroidism-induced myocardial fibrosis in rats through stimulating autophagy and inhibiting TGF-β1/Smad2 pathway [J ] . Korean J Physiol Pharmacol , 2023 , 27 ( 1 ): 1 - 8 .
Hu J , Wang X , Cui X , et al . Quercetin prevents isoprenaline-induced myocardial fibrosis by promoting autophagy via regulating miR-223-3p/FOXO3 [J ] . Cell Cycle , 2021 , 20 ( 13 ): 1253 - 1269 .
Bernard M , Dieudé M , Yang B , et al . Autophagy fosters myofibroblast differentiation through MTORC2 activation and downstream upregulation of CTGF [J ] . Autophagy , 2014 , 10 ( 12 ): 2193 - 2207 .
Yang T , Yang Q , Lai Q , et al . AP39 inhibits ferroptosis by inhibiting mitochondrial autophagy through the PINK1/parkin pathway to improve myocardial fibrosis with myocardial infarction [J ] . Biomed Pharmacother , 2023 , 165 : 115195 .
Boise LH , Collins CM . Salmonella -induced cell death:apoptosis,necrosis or programmed cell death? [J ] . Trends Microbiol , 2001 , 9 ( 2 ): 64 - 67 .
Burdette BE , Esparza AN , Zhu H , et al . Gasdermin D in pyroptosis [J ] . Acta Pharm Sin B , 2021 , 11 ( 9 ): 2768 - 2782 .
de Vasconcelos NM , Van Opdenbosch N , Van Gorp H , et al . Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture [J ] . Cell Death Differ , 2019 , 26 ( 1 ): 146 - 161 .
Rühl S , Shkarina K , Demarco B , et al . ESCRT-dependent membrane repair negatively regulates pyroptosis downstream of GSDMD activation [J ] . Science , 2018 , 362 ( 6417 ): 956 - 960 .
Qian J , Hu Y , Zhang X , et al . Mycobacterium tuberculosis PE_PGRS19 induces pyroptosis through a non-classical caspase-11/GSDMD pathway in macrophages [J ] . Microorganisms , 2022 , 10 ( 12 ): 2473 .
Kayagaki N , Warming S , Lamkanfi M , et al . Non-canonical inflammasome activation targets caspase-11 [J ] . Nature , 2011 , 479 ( 7371 ): 117 - 121 .
Gong WH , Shi Y , Ren JJ . Research progresses of molecular mechanism of pyroptosis and its related diseases [J ] . Immunobiology , 2020 , 225 ( 2 ): 151884 .
Zhang L , Jiang YH , Fan CD , et al . MCC950 attenuates doxorubicin-induced myocardial injury in vivo and in vitro by inhibiting NLRP3-mediated pyroptosis [J ] . Biomed Pharmacother , 2021 , 143 : 112133 .
Li Z , Chen K , Zhu YZ . Leonurine inhibits cardiomyocyte pyroptosis to attenuate cardiac fibrosis via the TGF-β/Smad2 signalling pathway [J ] . PLoS One , 2022 , 17 ( 11 ): e0275258 .
Zhang J , Wang G , Shi Y , et al . Growth differentiation factor 11 regulates high glucose-induced cardiomyocyte pyroptosis and diabetic cardiomyopathy by inhibiting inflammasome activation [J ] . Cardiovasc Diabetol , 2024 , 23 ( 1 ): 160 .
Ruan H , Li X , Zhou L , et al . Melatonin decreases GSDME mediated mesothelial cell pyroptosis and prevents peritoneal fibrosis and ultrafiltration failure [J ] . Sci China Life Sci , 2024 , 67 ( 2 ): 360 - 378 .
Laster SM , Wood JG , Gooding LR . Tumor necrosis factor can induce both apoptic and necrotic forms of cell lysis [J ] . J Immunol , 1988 , 141 ( 8 ): 2629 - 2634 .
Sun L , Wang X . A new kind of cell suicide:mechanisms and functions of programmed necrosis [J ] . Trends Biochem Sci , 2014 , 39 ( 12 ): 587 - 593 .
Cai Z , Jitkaew S , Zhao J , et al . Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis [J ] . Nat Cell Biol , 2014 , 16 ( 1 ): 55 - 65 .
McComb S , Cessford E , Alturki NA , et al . Type-I interferon signaling through ISGF3 complex is required for sustained Rip3 activation and necroptosis in macrophages [J ] . Proc Natl Acad Sci USA , 2014 , 111 ( 31 ): E3206 - E3213 .
Petrie EJ , Czabotar PE , Murphy JM . The structural basis of necroptotic cell death signaling [J ] . Trends Biochem Sci , 2019 , 44 ( 1 ): 53 - 63 .
Hu S , Gao Y , Gao R , et al . The selective STING inhibitor H-151 preserves myocardial function and ameliorates cardiac fibrosis in murine myocardial infarction [J ] . Int Immunopharmacol , 2022 , 107 : 108658 .
Oerlemans MIFJ , Liu J , Arslan F , et al . Inhibition of RIP1-dependent necrosis prevents adverse cardiac remodeling after myocardial ischemia–reperfusion in vivo [J ] . Basic Res Cardiol , 2012 , 107 ( 4 ): 270 .
Kang P , Wang J , Fang D , et al . Activation of ALDH2 attenuates high glucose induced rat cardiomyocyte fibrosis and necroptosis [J ] . Free Radic Biol Med , 2020 , 146 : 198 - 210 .
Dixon SJ , Lemberg KM , Lamprecht MR , et al . Ferroptosis:an iron-dependent form of nonapoptotic cell death [J ] . Cell , 2012 , 149 ( 5 ): 1060 - 1072 .
Jiang X , Stockwell BR , Conrad M . Ferroptosis:mechanisms,biology and role in disease [J ] . Nat Rev Mol Cell Biol , 2021 , 22 ( 4 ): 266 - 282 .
Doll S , Freitas FP , Shah R , et al . FSP1 is a glutathione-independent ferroptosis suppressor [J ] . Nature , 2019 , 575 ( 7784 ): 693 - 698 .
Wu JR , Tuo QZ , Lei P . Ferroptosis,a recent defined form of critical cell death in neurological disorders [J ] . J Mol Neurosci , 2018 , 66 ( 2 ): 197 - 206 .
Parker JL , Deme JC , Kolokouris D , et al . Molecular basis for redox control by the human cystine/glutamate antiporter system xc [J ] . Nat Commun , 2021 , 12 ( 1 ): 7147 .
Dixon SJ , Olzmann JA . The cell biology of ferroptosis [J ] . Nat Rev Mol Cell Biol , 2024 , 25 ( 6 ): 424 - 442 .
Liu D , Yang M , Yao Y , et al . Cardiac fibroblasts promote ferroptosis in atrial fibrillation by secreting exo-miR-23a-3p targeting SLC7A11 [J ] . Oxid Med Cell Longev , 2022 , 2022 : 3961495 .
Wang J , Deng B , Liu Q , et al . Pyroptosis and ferroptosis induced by mixed lineage kinase 3(MLK3) signaling in cardiomyocytes are essential for myocardial fibrosis in response to pressure overload [J ] . Cell Death Dis , 2020 , 11 ( 7 ): 574 .
Quagliariello V , De Laurentiis M , Rea D , et al . The SGLT-2 inhibitor empagliflozin improves myocardial strain,reduces cardiac fibrosis and pro-inflammatory cytokines in non-diabetic mice treated with doxorubicin [J ] . Cardiovasc Diabetol , 2021 , 20 ( 1 ): 150 .
Tsvetkov P , Coy S , Petrova B , et al . Copper induces cell death by targeting lipoylated TCA cycle proteins [J ] . Science , 2022 , 375 ( 6586 ): 1254 - 1261 .
Chen L , Min J , Wang F . Copper homeostasis and cuproptosis in health and disease [J ] . Signal Transduct Target Ther , 2022 , 7 ( 1 ): 378 .
Xue Q , Kang R , Klionsky DJ , et al . Copper metabolism in cell death and autophagy [J ] . Autophagy , 2023 , 19 ( 8 ): 2175 - 2195 .
Wang S , Zheng C , Huang YM , et al . Betel quid may stimulate oral submucous fibrosis by inducing increased mitochondrial reactive oxygen species generation via copper overload [J ] . Med Hypotheses , 2023 , 174 : 111067 .
Chen YF , Qi RQ , Song JW , et al . Sirtuin 7 ameliorates cuproptosis,myocardial remodeling and heart dysfunction in hypertension through the modulation of YAP/ATP7A signaling [J ] . Apoptosis , 2024 , 29 ( 11 ): 2161 - 2182 .
Pan M , Cheng ZW , Huang CG , et al . Long-term exposure to copper induces mitochondria-mediated apoptosis in mouse hearts [J ] . Ecotoxicol Environ Saf , 2022 , 234 : 113329 .
Niu YY , Zhang YY , Zhu Z , et al . Elevated intracellular copper contributes a unique role to kidney fibrosis by lysyl oxidase mediated matrix crosslinking [J ] . Cell Death Dis , 2020 , 11 ( 3 ): 211 .
Fritsch M , Günther SD , Schwarzer R , et al . Caspase-8 is the molecular switch for apoptosis,necroptosis and pyroptosis [J ] . Nature , 2019 , 575 ( 7784 ): 683 - 687 .
Fritsch M , Günther SD , Schwarzer R , et al . Caspase-8 is the molecular switch for apoptosis,necroptosis and pyroptosis [J ] . Nature , 2019 , 575 ( 7784 ): 683 - 687 .
Cristaldi M , Buscetta M , Cimino M , et al . Caspase-8 activation by cigarette smoke induces pro-inflammatory cell death of human macrophages exposed to lipopolysaccharide [J ] . Cell Death Dis , 2023 , 14 ( 11 ): 773 .
Neitemeier S , Jelinek A , Laino V , et al . BID links ferroptosis to mitochondrial cell death pathways [J ] . Redox Biol , 2017 , 12 : 558 - 570 .
Gao M , Monian P , Pan Q , et al . Ferroptosis is an autophagic cell death process [J ] . Cell Res , 2016 , 26 ( 9 ): 1021 - 1032 .
Xiong M , Wang MS , Liu XF , et al . Quercetin inhibits oligodendrocytes ferroptosis by blocking NCOA4-mediated ferritinophagy [J ] . Int Immunopharmacol , 2025 , 150 : 114152 .
Qian S , Long Y , Tan G , et al . Programmed cell death:molecular mechanisms,biological functions,diseases,and therapeutic targets [J ] . MedComm (2020), 2024 , 5 ( 12 ): e70024 .
0
浏览量
1
下载量
0
CSCD
关联资源
相关文章
相关作者
相关机构
京公网安备11010802024621