窦文朝,彭瑜,张钲

• 1:兰州大学第一临床医学院
• 2:兰州大学第一医院心脏中心
• 3:甘肃省心血管病临床医学研究中心

摘要(Abstract)：

经皮冠状动脉介入治疗（PCI）是当今冠状动脉疾病的主要治疗方法。尽管药物洗脱支架（DES）技术不断发展，在第二代DES置入后，仍有约10%左右的患者发生支架内再狭窄（ISR）。ISR的特征是支架内进行性管腔狭窄，这是PCI诱导的目标节段动脉壁机械损伤的结果。ISR的病理生理机制尚不清楚，但目前认为血管炎症、血小板活化、血管平滑肌细胞（VSMCs）增殖和迁移以及细胞外基质重塑是导致动脉腔重新狭窄的新内膜增生的原因，从而形成ISR的发生和演变。因此，本综述探讨了PCI术后表观遗传调控下ISR的分子病理机制，为抑制VSMCs增殖、迁移而不影响血管内膜再内皮化寻找更为精准、有效的靶点以预防ISR的发生发展。

关键词(KeyWords)： 经皮冠状动脉介入治疗;支架内再狭窄;表观遗传调控;信号通路

Abstract:

Keywords:

基金项目(Foundation): 甘肃省心血管病临床医学研究中心（18JR2FA005）

作者(Author): 窦文朝,彭瑜,张钲

参考文献(References)：

• [1]Oikonomou EK,Antoniades C.The role of adipose tissue in cardiovascular health and disease[J].Nat Rev Cardiol,2019,16(2):83-99.DOI:10.1038/s41569-018-0097-6.
• [2]刘明波，何新叶，杨晓红，等.《中国心血管健康与疾病报告2023》概要（心血管疾病流行及介入诊疗状况）[J].中国介入心脏病学杂志，2024,32(10):541-5 5 0.DOI:10.3969/j.issn.1004-8812.2024.10.001.
• [3]郝伟，赵晨，胡思宁，等.冠状动脉药物洗脱支架内再狭窄的最新研究进展[J].中国介入心脏病学杂志，2023,31(1):63-68.DOI:10.3969/j.issn.1004-8812.2023.01.010.
• [4]何攀，陈海威，杨俊杰，等.准分子激光冠状动脉成形术联合药物涂层球囊在复发性支架内再狭窄病变中的运用探讨[J].中国介入心脏病学杂志，2023,31(11):849-854.DOI:10.3969/j.issn.1004-8812.2023.11.007.
• [5]韩燕，袁晓航，高磊.光学相干断层成像指导冠状动脉支架内再狭窄介入治疗进展[J].中国介入心脏病学杂志，2023,31(5):356-361.DOI:10.3969/j.issn.1004-8812.2023.05.006.
• [6]Gao JW,He WB,Xie CM,et al.Aldosterone enhances high phosphate-induced vascular calcification through inhibition of AMPK-mediated autophagy[J].J Cell Mol Med,2020,24(23):13648-13659.DOI:10.1111/jcmm.15813.
• [7]Kamiya A,Togawa T.Adaptive regulation of wall shear stress to flow change in the canine carotid artery[J].Am J Physiol,1980,239(1):H14-H21.DOI:1 0.1152/ajpheart.1980.239.1.H14.
• [8]Morera L,Lübbert M,Jung M.Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy[J].Clin Epigenetics,2016,8:57.DOI:10.1186/s13148-016-0223-4.
• [9]Liu R,Jin Y,Tang WH,et al.Ten-eleven translocation-2(TET2)is a master regulator of smooth muscle cell plasticity[J].Circulation,2013,128(18):2047-2057.DOI:10.1161/CIRCULATIONAHA.11 3.002887.
• [10]Park SJ,Kang SJ,Virmani R,et al.In-stent neoatherosclerosis:a final common pathway of late stent failure[J].Am Coll Cardiol,2012,59(23):2051-2057.DOI:10.1016/j.jacc.2011.10.909.
• [11]Pons D,de Vries FR,van den Elsen PJ,et al.Epigenetic histone acetylation modifiers in vascular remodelling:new targets for therapy in cardiovascular disease[J].Eur Heart J,2009,30(3):266-277.DOI:10.1093/eurhear tj/ehn603.
• [12]Jukema JW,Verschuren JJ,Ahmed TA,et al.Restenosis after PCI.Part 1:pathophysiology and risk factors[J].Nat Rev Cardiol,2011,9(1):53-62.DOI:10.1038/nrcardio.2011.132.
• [13]Dangas GD,Claessen BE,Caixeta A,et al.In-stent restenosis in the drug-eluting stent era[J].J Am Coll Cardiol,2010,56(23):1897-1907.DOI:10.1016/j.jacc.2010.07.028.
• [14]Hou J,Deng Q,Liu S,et al.Plasma proteome profiling of patients with in-stent restenosis by tandem mass tag-based quantitative proteomics approach[J].Front Cardiovasc Med,2022,9:793405.DOI:10.3389/fcvm.2022.793405.
• [15]Waksman R,Iantorno M.Refractory in-stent restenosis:improving outcomes by standardizing our approach[J].Curr Cardiol Rep,2018,20(12):140.DOI:10.1007/s11886-018-1076-6.
• [16]Alfonso F,Cuesta J,Pérez-Vizcayno MJ,et al.Bioresorbable vascular scaff olds for patients with in-stent restenosis:the RIBSVI study[J].JACC Cardiovasc Interv,2017,10(18):1841-1851.DOI:10.1016/j.jcin.20 17.06.064.
• [17]Waksman R.A new generation of drug-eluting stents:Indications and outcomes of bioresorbable vascular scaffolds[J].Cleve Clin J Med,2017,84(12 Suppl 4):e20-e24.DOI:10.3949/ccjm.84.s4.05.
• [18]Puricel S,Arroyo D,Corpataux N,et al.Comparison of everolimus-and biolimus-eluting coronarystents with everolimus-eluting bioresorbable vascular scaff olds[J].JAm Coll Cardiol,2015,65(8):791-801.DOI:10.1016/j.jacc.2014.12.017.
• [19]Ali I,Conrad RJ,Verdin E,et al.Lysine acetylation goes global:from epigenetics to metabolism and therapeutics[J].Chem Rev,2018,118 (3):1216-1252.DOI:10.10 21/acs.che mrev.7b00181.
• [20]Li L,Zhang HN,Chen HZ,et al.SIRT1 acts as a modulator of neointima formation following vascular injury in mice[J].Circ Res,2011,108(10):1180-1189.DOI:10.1161/CIRCRESAHA.110.237875.
• [21]Zhang X,Liu L,Yuan X,et al.JMJD3 in the regulation of human diseases[J].Protein Cell,2019,10 (12):864-882.DOI:10.1007/s13238-019-0653-9.
• [22]Peng J,Tang ZH,Ren Z,et al.TET2 protects against ox LDL-induced HUVEC dysfunction by upregulating the CSE/H(2)Ssystem[J].Front Pharmacol,2017,8:486.DOI:10.3389/fphar.2017.00486.
• [23]Chen K,Jin HJ,Wu ZH,et al.Glucagon-like peptide-1receptor agonist exendin 4 ameliorates diabetes-associated vascular calcification by regulating mitophagy through the AMPKsignaling path way[J].Mol Med,2024,30(1):58.DOI:10.1186/s10020-024-00817-8.
• [24]Furmanik M,Chatrou M,van Gorp R,et al.Reactive oxygenforming Nox5 links vascular smooth muscle cell phenotypic switching and extracellular vesicle-mediated vascular calcification[J].Circ Res,2020,127(7):911-927.DOI:10.1161/CIRCRESAHA.119.316159.
• [25]Gareri C,De Rosa S,IndolfiC.Micro RNAs for restenosis and thrombosis after vascular injury[J].Circ Res,2016,118(7):1170-1184.DOI:10.1161/CIRCRESAHA.115.308237.
• [26]Peng J,Yang Q,Li AF,et al.Tet methylcytosine dioxygenase2 inhibits atherosclerosis via upregulation of autophagy in Apo E-/-mice[J].Oncotarget,2016,7(47):76423-76436.DOI:10.18632/oncotar get.13121.
• [27]Romano G,Veneziano D,Acunzo M,et al.Small non-coding RNA and cancer[J].Carcinogenesis,2017,38(5):485-491.DOI:10.1093/carcin/bgx026.
• [28]Yu S,Chen X,Xiu M,et al.The regulation of Jmjd3 upon the expression of NF-κB downstream inflammatory genes in LPS activated vascular endothelial cells[J].Biochem Biophys Res Commun,2017,485 (1):62-68.DOI:10.1016/j.bbrc.2017.02.020.
• [29]Li M,Fukagawa NK.Age-related changes in redox signaling and VSMC function[J].Antioxid Redox Signal,2010,12(5):641-655.DOI:10.1089/ars.2009.2854.
• [30]Vendrov AE,Sumida A,Canugovi C,et al.NOXA1-dependent NADPH oxidase regulates redox signaling and phenotype of vascular smooth muscle cell during atherogenesis[J].Redox Biol,2019,21:101063.DOI:10.1016/j.redox.2018.11.021.
• [31]Sundqvist MO,W?rme J,Hofmann R,et al.Helicobacter pylori virulence factor cytotoxin-associated Gene A (Cag A)induces vascular calcification in coronary artery smooth muscle cells[J].Int J Mol Sci,2023,24(6):5392.DOI:10.3390/ijms24065392.
• [32]Yang X,Yang Y,Guo J,et al.Targeting the epigenome in in-stent restenosis:from mechanisms to therapy[J].Mol Ther Nucleic Acids,2021,23:1136-1160.DOI:10.1016/j.omtn.2021.01.024.
• [33]Lu QB,Wan MY,Wang PY,et al.Chicoric acid prevents PDGF-BB-induced VSMC dedifferentiation,proliferation and migration by suppressing ROS/NFκB/m TOR/P70S6K signaling cascade[J].Redox Biol,2018,14:656-668.DOI:10.1016/j.redox.2017.11.012.
• [34]Han JH,Park HS,Lee DH,et al.Regulation of autophagy by controlling Erk1/2 and m TOR for platelet-derived growth factorBB-mediated vascular smooth muscle cell phenotype shift[J].Life Sci,2021,267:118978.DOI:10.1016/j.lfs.2020.118978.
• [35]Hwang YJ,Park JH,Cho DH.Activation of AMPKb y telmisartan decreases basal and PDGF-stimulated VSMCproliferation via inhibiting the m TOR/p70S6K signaling axis[J].J Korean Med Sci,2020,35(35):e289.DOI:10.3346/jkms.2020.35.e289.
• [36]Qi W,Li Q,Liew CW,et al.SHP-1 activation inhibits vascular smooth muscle cell proliferation and intimal hyperplasia in a rodent model of insulin resistance and diabetes[J].Diabetologia,2017,60(3):585-596.DOI:10.1007/s00125-016-4159-1.
• [37]Zhang Y,Zeng C.Role of DNA methylation in cardiovascular diseases[J].Clin Exp Hypertens,2016,38 (3):261-267.DOI:10.3109/10641963.2015.1107087.
• [38]Wilson M,Al-Hamid A,Abbas I,et al.Identification o f diagnostic biomarkers used in the diagnosis of cardiovascular diseases and diabetes mellitus:a systematic review of quantitative studies[J].Diabetes Obes Metab,2024,26(8):3009-3019.DOI:10.1111/dom.15593.
• [39]Chen NN,Zhou KF,Miao Z,et al.Exosomes regulate doxorubicin resistance in breast cancer via mi R-34a-5p/NOTCH1[J].Mol Cell Probes,2024,76:101964.DOI:10.1016/j.mcp.2024.101964.
• [40]Qian HL,Chen SY,Jia F,et al.Spongy skin”as arobust strategy to deliver 4-octyl itaconate for conducting dual-regulation against in-stent restenosis[J].Biomaterials,2023,296:122069.DOI:10.1016/j.biomaterials.2023.122069.
• [41]Wang Z,Niu Q,Peng X,et al.Mitofusin 2 ameliorates aortic remodeling by suppressing ras/raf/ERK pathway and regulating mitochondrial function in vascular smooth muscle cells[J].Int J Cardio,2015,178:165-167.DOI:10.1016/j.ijcard.2014.10.122.
• [42]Yang F,Chen Q,He S,et al.mi R-22 is a novel mediator of vascular smooth muscle cell phenotypic modulation and neointima formation[J].Circulation,2018,137(17):1824-1841.DOI:10.11 61/CIRCULATIONAHA.117.027799.
• [43]Zhao H,Wen G,Huang Y,et al.Micro RNA-22 regulates smooth muscle cell differentiation from stem cells by targeting methyl Cp G-binding protein 2[J].Arterioscler Thromb Vasc Biol,2015,35(4):918-929.DOI:10.1161/ATVBAHA.114.305212.
• [44]Niu K,Zhang C,Yang M,et al.Small nucleolar RNA host gene18 controls vascular smooth muscle cell contractile phenotype and neointimal hyperplasia[J].Cardiovasc Res,2024,120(7):796-810.DOI:10.1093/cvr/cvae055.
• [45]Wang J,Qian HL,Chen SY,et al.mi R-22 eluting cardiovascular stent based on a self-healable spongy coating inhibits in-stent restenosis[J].Bioact Mater,2021,6(12):4686-4696.DOI:10.1016/j.bioact mat.2021.04.037.