心肌梗死中铁死亡标志物研究进展

doi:10.16150/j.1671-2870.2023.02.015

摘要/Abstract

摘要：

心肌梗死诊治进展使部分患者的预后获得明显改善，但患者的总体生存率仍不理想。深入研究心肌缺血再灌注后损伤机制可能改善研究的方向。铁死亡作为近年来新发现的调节性细胞死亡方式，其是主要由脂质过氧化引起的铁依赖性细胞死亡，特点是细胞死亡涉及脂质过氧化物和活性氧的积累。铁死亡被认为在缺血再灌注损伤中发挥重要作用。研究提示心肌梗死后的铁死亡相关标志物出现变化包括，细胞内铁代谢中的线粒体铁蛋白(mitochondrial ferritin, FtMt)缺失，谷胱甘肽代谢途径的末端分子谷胱甘肽过氧化物酶4（glutathione peroxidase 4 ，Gpx4）水平下降、谷胱甘肽合成中氨基酸逆向转运蛋白胱氨酸/谷氨酸转运体系统(cystine/glutamate transporter, System xc^-, SXc^-）功能下降和脂质代谢酶酰基辅酶A合成酶长链家族成员4 (acyl-CoA synthetase long-chain family member 4, ACSL4)的过度表达，导致了心肌梗死后的氧化应激、炎症反应，加重心肌缺血再灌注损伤。FtMt、Gpx4、SXc^-和ACSL4这4种生物标志物是心肌梗死后铁死亡相关诊治的重要研究靶点，值得深入研究。

关键词: 心肌梗死, 铁死亡, 生物标志物

Abstract:

The development in diagnosis and treatment of myocardial infarction has significantly improved the prognosis of some patients, while the overall survival rate of patients remains much room for improvement. Further research of the mechanism of injury after myocardial ischemia and reperfusion may explore new directions of research. As a newly discovered form of regulated cell death, ferroptosis, an iron-dependent cell death caused by lipid peroxidation, which has been characterized by cell death involving the accumulation of lipid peroxides and reactive oxygen species. Ferroptosis, which has been acknowledged to play an important role in ischemia-reperfusion injury. Studies suggest that iron death-related marker changes after myocardial infarction (MI), including hiatus of mitochondrial ferritin (FtMt) in intracellular iron metabolism, decreased levels of glutathione peroxidase 4 (Gpx4), a terminal molecule of glutathione metabolism pathway, insufficient use of antiporter cystine/glutathione synthesis (SXc^-) in glutathione synthesis, and overexpression of Acyl-CoA synthetase long-chain family member 4 (ACSL4) can lead to oxidative stress, inflammatory response, cardiomyocyte injury after myocardial infarction, and can aggravate the myocardial ischemia-reperfusion injury. The four biological markers mentioned above, FtMt, Gpx4, SXc^- and ACSL4, are important research targets for the diagnosis and treatment of iron death after MI, which may deserve further study.

Key words: Myocardial infarction, Ferroptosis, Biological marker

中图分类号:

R542.23

常宇宸, 李京波. 心肌梗死中铁死亡标志物研究进展[J]. 诊断学理论与实践, 2023, 22(02): 197-202.

CHANG Yuchen, LI Jingbo. Advances in biological markers of ferroptosis in myocardial infarction[J]. Journal of Diagnostics Concepts & Practice, 2023, 22(02): 197-202.

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参考文献 39

[1]	王增武. 《基层冠心病与缺血性脑卒中共患管理专家共识2022》解读[J]. 中国心血管杂志, 2022, 27(5):411-416.
	WANG Z W. Interpretation of 2022 Expert Consensus on the Management of Coronary Heart Disease with Ische-mic Stroke in Community[J]. Chin J Cardiovasc Med, 2022, 27(5):411-416.
[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2021概要[J]. 心脑血管病防治, 2022, 22(4):20-36,40.
	The Writing Committee of the Report on Cardiovascular Health and Diseases in China. Special Report Report on cardiovascular health and diseases in China 2021: an updated summary[J]. Prev Treat Cardio-Cereb-Vascular Dis, 2022, 22(4):20-36,40.
[3]	WU W, CHANG S, WU Q, et al. Mitochondrial ferritin protects the murine myocardium from acute exhaustive exercise injury[J]. Cell Death Dis, 2016, 7(11):e2475. doi: 10.1038/cddis.2016.372
[4]	WANG L, WANG L, DAI Z, et al. Lack of mitochondrial ferritin aggravated neurological deficits via enhancing oxidative stress in a traumatic brain injury murine model[J]. Biosci Rep, 2017, 37(6):BSR20170942.
[5]	DOLMA S, LESSNICK S L, HAHN W C, et al. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells[J]. Cancer Cell, 2003, 3(3):285-296. doi: 10.1016/s1535-6108(03)00050-3 pmid: 12676586
[6]	DIXON S J, LEMBERG K M, LAMPRECHT M R, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death[J]. Cell, 2012, 149(5):1060-1072. doi: 10.1016/j.cell.2012.03.042 pmid: 22632970
[7]	YANG W S, STOCKWELL B R. Synthetic lethal scree-ning identifies compounds activating iron-dependent, non-apoptotic cell death in oncogenic-RAS-harboring cancer cells[J]. Chem Biol, 2008, 15(3):234-245. doi: 10.1016/j.chembiol.2008.02.010 URL
[8]	LI X, LIANG J, QU L, et al. Exploring the role of ferroptosis in the doxorubicin-induced chronic cardiotoxicity using a murine model[J]. Chem Biol Interact, 2022, 363:110008. doi: 10.1016/j.cbi.2022.110008 URL
[9]	LV J, HOU B, SONG J, et al. The Relationship Between Ferroptosis and Diseases[J]. J Multidiscip Healthc, 2022, 15:2261-2275. doi: 10.2147/JMDH.S382643 pmid: 36225859
[10]	ZHENG Y, QIN C, LI F, et al. Self-assembled thioether-bridged paclitaxel-dihydroartemisinin prodrug for amplified antitumor efficacy-based cancer ferroptotic-chemotherapy[J]. Biomater Sci. 2023 May 2;11(9):3321-3334.
[11]	MAGTANONG L, KO P J, DIXON S J. Emerging roles for lipids in non-apoptotic cell death[J]. Cell Death Differ, 2016, 23(7):1099-1109. doi: 10.1038/cdd.2016.25 pmid: 26967968
[12]	LILLO-MOYA J, ROJAS-SOLÉ C, MUÑOZ-SALAMANCA D, et al. Targeting Ferroptosis against Ischemia/Reperfusion Cardiac Injury[J]. Antioxidants (Basel), 2021, 10(5):667.
[13]	MACCARINELLI F, GAMMELLA E, ASPERTI M, et al. Mice lacking mitochondrial ferritin are more sensitive to doxorubicin-mediated cardiotoxicity[J]. J Mol Med (Berl), 2014, 92(8):859-869. doi: 10.1007/s00109-014-1147-0 pmid: 24728422
[14]	GANZ T. Systemic iron homeostasis[J]. Physiol Rev, 2013, 93(4):1721-1741. doi: 10.1152/physrev.00008.2013 pmid: 24137020
[15]	GOZZELINO R, SOARES M P. Coupling heme and iron metabolism via ferritin H chain[J]. Antioxid Redox Signal, 2014, 20(11):1754-1769. doi: 10.1089/ars.2013.5666 URL
[16]	PHAM C G, BUBICI C, ZAZZERONI F, et al. Ferritin heavy chain upregulation by NF-kappaB inhibits TNFalpha-induced apoptosis by suppressing reactive oxygen species[J]. Cell, 2004, 119(4):529-542. doi: 10.1016/j.cell.2004.10.017 pmid: 15537542
[17]	CHEN X, YU C, KANG R, et al. Iron Metabolism in Ferroptosis[J]. Front Cell Dev Biol, 2020, 8:590226. doi: 10.3389/fcell.2020.590226 URL
[18]	WANG P, CUI Y, REN Q, et al. Mitochondrial ferritin attenuates cerebral ischaemia/reperfusion injury by inhibiting ferroptosis[J]. Cell Death Dis, 2021, 12(5):447. doi: 10.1038/s41419-021-03725-5 pmid: 33953171
[19]	WANG P, CUI Y, REN Q, et al. Mitochondrial ferritin attenuates cerebral ischaemia/reperfusion injury by inhibi-ting ferroptosis[J]. Cell Death Dis, 2021, 12(5):447. doi: 10.1038/s41419-021-03725-5
[20]	WU W, CHANG S, WU Q, et al. Mitochondrial ferritin protects the murine myocardium from acute exhaustive exercise injury[J]. Cell Death Dis, 2016, 7(11):e2475. doi: 10.1038/cddis.2016.372
[21]	MACCARINELLI F, GAMMELLA E, ASPERTI M, et al. Mice lacking mitochondrial ferritin are more sensitive to doxorubicin-mediated cardiotoxicity[J]. J Mol Med (Berl), 2014, 92(8):859-869. doi: 10.1007/s00109-014-1147-0 pmid: 24728422
[22]	FUHRMANN D C, MONDORF A, BEIFUß J, et al. Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis[J]. Redox Biol, 2020, 36:101670. doi: 10.1016/j.redox.2020.101670 URL
[23]	CAMPANELLA A, ROVELLI E, SANTAMBROGIO P, et al. Mitochondrial ferritin limits oxidative damage regulating mitochondrial iron availability: hypothesis for a protective role in Friedreich ataxia[J]. Hum Mol Genet, 2009, 18(1):1-11. doi: 10.1093/hmg/ddn308 pmid: 18815198
[24]	XIE K, MO Y, YUE E, et al. Exosomes derived from M2-type microglia ameliorate oxygen-glucose deprivation/reoxygenation-induced HT22 cell injury by regulating miR-124-3p/NCOA4-mediated ferroptosis[J]. Heliyon, 2023, 9(7):e17592. doi: 10.1016/j.heliyon.2023.e17592 URL
[25]	XU W, SUN T, WANG J, et al. GPX4 Alleviates Diabetes Mellitus-Induced Erectile Dysfunction by Inhibiting Ferroptosis[J]. Antioxidants (Basel), 2022, 11(10):1896.
[26]	INGOLD I, BERNDT C, SCHMITT S, et al. Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis[J]. Cell, 2018, 172(3):409-422. doi: S0092-8674(17)31438-1 pmid: 29290465
[27]	HOLMSTRÖM K M, FINKEL T. Cellular mechanisms and physiological consequences of redox-dependent signalling[J]. Nat Rev Mol Cell Biol, 2014, 15(6):411-421. doi: 10.1038/nrm3801
[28]	XUE Q, YAN D, CHEN X, et al. Copper-dependent autophagic degradation of GPX4 drives ferroptosis[J]. Autophagy, 2023, 19(7):1982-1996. doi: 10.1080/15548627.2023.2165323 URL
[29]	SHIMADA K, SKOUTA R, KAPLAN A, et al. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis[J]. Nat Chem Biol, 2016, 12(7):497-503. doi: 10.1038/nchembio.2079 pmid: 27159577
[30]	YANG L, CHEN X, YANG Q, et al. Broad Spectrum Deubiquitinase Inhibition Induces Both Apoptosis and Ferroptosis in Cancer Cells[J]. Front Oncol, 2020, 10:949. doi: 10.3389/fonc.2020.00949 pmid: 32596160
[31]	LIU Y, WANG Y, LIU J, et al. Interplay between MTOR and GPX4 signaling modulates autophagy-dependent ferroptotic cancer cell death[J]. Cancer Gene Ther, 2021, 28(1-2):55-63. doi: 10.1038/s41417-020-0182-y
[32]	JIANG Y, QIAO Y, HE D, et al. Adaptor protein HIP-55-mediated signalosome protects against ferroptosis in myocardial infarction[J]. Cell Death Differ, 2023, 30(3):825-838. doi: 10.1038/s41418-022-01110-z pmid: 36639542
[33]	BRIDGES R J, NATALE N R, PATEL S A. System xc⁻ cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS[J]. Br J Pharmacol, 2012, 165(1):20-34. doi: 10.1111/j.1476-5381.2011.01480.x URL
[34]	LI Y, YAN J, ZHAO Q, et al. ATF3 promotes ferroptosis in sorafenib-induced cardiotoxicity by suppressing Slc7a11 expression[J]. Front Pharmacol, 2022, 13:904314. doi: 10.3389/fphar.2022.904314 URL
[35]	HUANG Y B, JIANG L, LIU X Q, et al. Melatonin Allevia-tes Acute Kidney Injury by Inhibiting NRF2/Slc7a11 Axis-Mediated Ferroptosis[J]. Oxid Med Cell Longev, 2022, 2022:4776243.
[36]	LIU T, SHU J, LIU Y, et al. Liu T, Shu J, Li L, et al. Atorvastatin attenuates ferroptosis-dependent myocardial injury and inflammation following coronary microembolization via the Hif1a/Ptgs2 pathway[J]. Front Pharmacol, 2022, 13:1057583. doi: 10.3389/fphar.2022.1057583 URL
[37]	LI Y, FENG D, WANG Z, et al. Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion[J]. Cell Death Differ, 2019, 26(11):2284-2299. doi: 10.1038/s41418-019-0299-4 pmid: 30737476
[38]	DOLL S, PRONETH B, TYURINA Y Y, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition[J]. Nat Chem Biol, 2017, 13(1):91-98. doi: 10.1038/nchembio.2239 pmid: 27842070
[39]	SUN L, WANG H, XU D, et al. Lapatinib induces mitochondrial dysfunction to enhance oxidative stress and ferroptosis in doxorubicin-induced cardiomyocytes via inhibition of PI3K/AKT signaling pathway[J]. Bioengineered, 2022, 13(1):48-60. doi: 10.1080/21655979.2021.2004980 pmid: 34898356

项目	形态学特征	生化特征
铁死亡	线粒体小而畸形，线粒体嵴减少或消失，细胞膜浓缩，线粒体外膜破裂，细胞核正常	铁代谢异常，脂质过氧化，ROS积累
细胞坏死	质膜破裂、固缩、核裂、核溶解、染色质解体、核轮廓消失和细胞成分溢出	ATP水平降低，DNA随机降解和扩散
细胞凋亡	细胞体积减少，细胞间连接消失，细胞骨架解体，染色质凝集，凋亡小体的形成	Caspase蛋白激活，DNA片段，生物大分子合成
细胞自噬	完整的细胞膜，细胞质中的囊泡样结构和自噬小体的形成	LC3-Ⅱ，P62、Beclin-1蛋白调控
细胞焦亡	细胞肿胀和增大，伴有气泡状突起，细胞膜破裂，内容物流出	炎症小体形成，Gasdermin D蛋白激活，促炎细胞因子释放