鸢尾素与心血管疾病的研究进展.pdf

412心血管康复医学杂志2 0 2 3 年8 月第3 2 卷第4期ChinJCardiovascRehabilMed，A u g u st2 0 2 3，V o l.3 2 No.4鸢尾素与心血管疾病的研究进展徐润秋，刘琦，侯静波摘要：鸢尾素是一种调节能量代谢的肌细胞因子及脂肪因子，其表达主要受运动调节。大量研究表明，鸢尾素不仅参与调节代谢稳态而且在心血管疾病（CVD）中具积极作用，如抗动脉粥样硬化、抗心肌缺血、抗缺血再灌注损伤、抑制心肌肥厚及纤维化等。本文就鸢尾素在CVD尤其是冠心病中的作用机制的研究进展作一综述。关键词：心血管疾病；冠心病；能量代谢文章编号：10 0 8-0 0 7 4（2 0 2 3）0 4-412-0 3Doi:10.3969/j.issn.1008-0074.2023.04.22Research progress of irisin in cardiovascular diseases/xU Run-qiu,LIU Qi,HOU Jing-bo/Department of Car-diology,Second Affiliated Hospital of Harbin Medical University,Harbin,Heilongjiang,150081,ChinaCorresponding author:HOU Jing-bo,E-mail:Abstract:Irisin is a kind of myocyte factor and adipokine that regulates energy metabolism,and its expression ismainly regulated by exercise.Lots of researches have indicated that irisin is not only involved in regulation of meta-bolic homeostasis,but also plays a positive role in cardiovascular diseases(CVD),such as anti-atherosclerosis,anti-myocardial ischemia,anti-ischemia reperfusion injury,and inhibition of myocardial hypertrophy and fibrosisetc.The present article makes a review on research progress of mechanism of irisin in CVD,especially in coronaryheart disease.Key words:Cardiovascular diseases;Coronary disease;Energy metabolism鸢尾素于2 0 12 年首次被发现，早期研究表明鸢尾素在机体接受运动刺激后由骨骼肌分泌，可增加能量消耗和调节糖脂代谢，近年来不断有研究发现鸢尾素具有重要的心血管保护作用。1鸢尾素概述鸢尾素发现于过表达转录辅因子过氧化物酶体增殖物激活受体共激活物因子1（PG C 1）的转基因小鼠中，PGC-1刺激跨膜蛋白型纤连蛋白域蛋白5（FNDC5）表达，FNDC5裂解产生鸢尾素，后者通过激活p38丝分裂原激活的蛋白激酶（MAPK）和细胞外信号调节激酶（ER K）途径上调解偶联蛋白1（UCP1）进而诱导脂肪组织褐变增加能量消耗。鸢尾素主要由骨骼肌细胞分泌，通常以一片式同二聚体的形式存在，可与细胞膜表面的整联蛋白尤其V5异二聚体结合发挥成骨及脂肪产热作用1I，运动是刺激鸢尾素生成的重要因素2 。2鸢尾素与糖脂代谢在糖脂代谢紊乱早期，鸢尾素水平往往代偿性升高以降低血糖及血脂，但是疾病状态下鸢尾素水平常降低。近期有研究表明特定的饮食方式可调节代谢综合征患者的鸢尾素水平3。2.1 血糖中图分类号：R54鸢尾素可作用于多种靶细胞调节葡萄糖稳态。脂肪组织中，鸢尾素可激活一磷酸腺苷蛋白激酶（AMPK）抑制巨噬细胞极化从而减轻脂肪组织炎症和胰岛素抵抗4。骨骼肌细胞中，鸢尾素可以通过AMPK5和p38MAPK6通路上调细胞葡萄糖转运蛋白4（GLUT4）表达从而增加葡萄糖的摄取及利用。肝细胞中，鸢尾素通过AMPK-磷脂酰肌醇-3-激酶（PI3K）一蛋白激酶B（A k t）途径抑制糖异生和促进糖原合成7 。鸢尾素还可通过ERK/p38MAPK信号通路促进胰腺细胞增殖8 。2.2血脂动物及细胞实验发现，鸢尾素可通过AMPK-胆固醇调节元件结合蛋白质2（SREBP2）信号轴抑制肝脏胆固醇合成9，也可通过上调肝、肠细胞三磷酸腺苷结合转运蛋白G5/G8(ABCG5/G8)的表达增加胆汁胆固醇转运和粪便胆固醇排出10 ，从而降低肥胖或糖尿病小鼠的甘油三酯（TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)水平。3鸢尾素与冠心病冠心病患者的循环鸢尾素水平比健康对照组显著降低，作者单位：哈尔滨医科大学附属第二医院心血管内科，黑龙江，哈尔滨150 0 8 1通讯作者：侯静波，E-mail：j i n g b o h o u 16 3.c o m文献标识码：A心血管康复医学杂志2 0 2 3 年8 月第3 2 卷第4期ChinJCardiovascRehabilMed，A u g u st2 0 2 3，V o l.3 2 No.4且与冠状动脉狭窄程度呈正相关。鸢尾素不仅可以通过调节糖脂代谢改善内皮功能，还可通过以下机制抑制冠心病进程。3.1抗动脉粥样硬化3.1.1血管内皮细胞：近年来发现鸢尾素可通过上调微小RNA-126-5p的表达，减轻高糖引起的内皮细胞损伤11；也可通过抑制活性氧（ROS）p 38 M A PK 核因子（NF)-kB通路12 或通过激活Akt-哺乳类动物雷帕霉素靶蛋白（m T O R）核因子E2相关因子2（Nrf2）通路13 减弱氧化型低密度脂蛋白（ox-LDL)，诱导血管炎症及内皮细胞调亡；还可抑制ROSNO D 样受体热蛋白结构区域3（NLR P3）炎性小体活化，减轻晚期糖基化终末产物（A G Es）诱导的血管炎症14。另外鸢尾素可减轻脂多糖(LPS）诱导微血管渗漏15。在上述研究的动物体内实验中，鸢尾素治疗可显著抑制载脂蛋白E缺陷小鼠颈动脉部分结扎模型的颈动脉内膜形成、斑块脂质沉积、巨噬细胞聚集以及炎症基因的表达11.13,141 。3.1.2巨噬细胞：鸢尾素通过抑制内质网调节激酶（PER K）真核起始因子2（e I F2）C/EBP同源转录因子（CHOP）和激活作用转录因子（ATF6）C H O P等内质网应激通路减轻ox-LDL诱导的巨噬细胞凋亡16 ，通过抑制MAPKT o ll样受体（TLR4）髓样分化因子（M y D 8 8）-NF-k B通路下调LPS刺激的巨噬细胞炎性因子的表达17 。3.1.3血管平滑肌细胞：鸢尾素通过激活信号转导子与转录激活子3（STAT3）阻止人血小板衍生生长因子BB（PD G F-BB）诱导的血管平滑肌细胞向增殖合成表型转化18 ，也通过激活AMPK沉默调节因子2 相关酶（SIRT）1信号通路减轻血管紧张素II（A n g）引起的血管平滑肌细胞表型转化191，还通过抑制NF-kBp65-NLRP3通路抑制ox-LDL诱导的平滑肌细胞泡沫化2 0 。3.1.4心肌细胞：鸢尾素可通过激活Akt信号通路对抗缺氧及脂毒性诱导的心肌细胞凋亡2 1，但最近有研究发现，在体外缺氧条件下过量的鸢尾素增加了心肌细胞凋亡2 2 。可见鸢尾素的抗心肌缺血作用有严格的浓度要求。3.2抗缺血再灌注损伤鸢尾素可通过激活p38MAPK超氧化物歧化酶1（SO D 1）通路2 3 或通过激活AMPK通路2 4 改善线粒体功能进而减轻缺氧复氧诱导的心肌细胞损伤以及缩小缺血再灌注的心肌梗死面积。前期的研究表明：对于行急诊经皮冠状动脉介入治疗（PC I）的急性ST段高型心肌梗死（STEMI）患者，远程缺血预处理（RIPC）可提高再灌注后鸢尾素水平，较高鸢尾素水平与梗死面积减小和左心室收缩功能增加相关，说明鸢尾素介导了RIPC的抗缺血再灌注损伤作用。3.3心肌梗死后修复鸢尾素通过激活ERK信号通路促进血管生成缩小心肌413梗死面积改善心脏功能2 5。鸢尾素还能提高心脏祖细胞和骨髓间充质干细胞移植入心肌梗死区的存活率，强化修复作用2 6.2 7 。4鸢尾素的其他心肌保护作用鸢尾素可改善高糖诱导的心肌细胞损伤2 8 和心脏纤维化2 9，可减轻AngI诱导心肌肥厚和纤维化30.31.32 ，可减轻肥胖引起的心肌肥大33，可纠正LPS诱导的脓毒性心功能障碍34，可减轻阿霉素所致的心脏毒性35。综上所述，鸢尾素很可能通过与整联蛋白结合改善高糖或AGEs或ox一LDL或LPS引起的内皮细胞损伤，也可抑制巨噬细胞功能发挥抗炎抗氧化特性，还可抑制血管平滑肌细胞表型转化和泡沫化，在抗缺血再灌注损伤和心肌梗死区修复等方面也有治疗作用，因此有理由认为鸢尾素具有积极的抗动脉粥样硬化作用。未来研究者们应积极探索疾病状态下鸢尾素水平降低的机制，在冠心病领域可探究鸢尾素对巨噬细胞泡沫化的影响及机制，而且如何将细胞和动物模型中的鸢尾素效应及信号传导机制在人类身上证实是即将面临的重大考验。参考文献：1J Kim H,Wrann CD,Jedrychowski M,et al.Irisin MediatesEffects on Bone and Fat via V Integrin Receptors JJ.Cell,2018，17 5（7)：17 56-17 6 8.2 Fox J,Rioux BV,Goulet EDB,et al.Effect of an acute ex-ercise bout on immediate post-exercise irisin concentration inadults:A meta-analysis J.Scand J Med Sci Sports,2018,28(1):16-28.3 Osella AR,Colaianni G,Correale M,et al.Irisin Serum Lev-els in Metabolic Syndrome Patients Treated with Three Differ-ent Diets:A Post-Hoc Analysis from a Randomized ControlledClinical Trial J.Nutrients，2 0 18，10 （7):8 44.4 Xiong XQ,Geng Z,Zhou B,et al.FNDC5 attenuates adi-pose tissue inflammation and insulin resistance via AMPK-me-diated macrophage polarization in obesity J.Metabolism,2018,83:31-41.5J Xin C,Liu J,Zhang J,et al.Irisin improves fatty acid oxida-tion and glucose utilization in type 2 diabetes by regulating theAMPK signaling pathway J.Int J Obes（Lo n d),2 0 16,40(3):443-451.6 Pang Y,Zhu H,Xu J,et al.-arrestin-2 is involved in iri-sin induced glucose metabolism in type 2 diabetes via p38 MAPKsignaling JJ.Exp Cell Res,2017,360(（2):199-2 0 4.7 Liu TY,Shi CX,Gao R,et al.Irisin inhibits hepatic gluco-neogenesis and increases glycogen synthesis via the PI3K/Aktpathway in type 2 diabetic mice and hepatocytes J.Clin Sci(Lond)，2 0 15，12 9(10):8 39-8 50.8 Liu S,Du F,Li X,et al.Effects and underlying mechanismsof irisin on the proliferation and apoptosis of pancreatic cellsJJ.PLoSOne,2017,12（4):e 0 17 549 8.4149 Tang H,Yu R,Liu S,et al.Irisin Inhibits Hepatic Choles-terol Synthesis via AMPK-SREBP2 Signaling JJ.EBioMedi-cine,2016,6:139-148.1o Li H,Shen J,Wu T,et al.Irisin Is Controlled by FarnesoidX Receptor and Regulates Cholesterol Homeostasis JJ.FrontPharmacol,2019,10:548.11 Zhang Y,Song H,Zhang Y,et al.Irisin Inhibits Athero-sclerosis by Promoting Endothelial Proliferation Through mi-croRNA126-5p J.J Am Heart Assoc,2016，5（9):e004031.12 Zhang Y,Mu Q,Zhou Z,et al.Protective Effect of Irisinon Atherosclerosis via Suppressing Oxidized Low Density Lipo-protein Induced Vascular Inflammation and Endothelial Dys-function JJ.PLoSOne,2016,11(6):e0158038.13J Zhang M,Xu Y,Jiang L.Irisin attenuates oxidized low-density lipoprotein impaired angiogenesis through AKT/mTOR/S6K1/Nrf2pathwayJ.JCellPhysiol,2019,234（10):18951-18962.14J Deng X,Huang W,Peng J,et al.Irisin Alleviates AdvancedGlycation End Products-Induced Inflammation and EndothelialDysfunction via Inhibiting ROS-NLRP3 Inflammasome Signa-lingJ.Inflammation，2 0 18，41（1):2 6 0-2 7 5.15 BiJ,Zhang J,Ren Y,et al.Exercise hormone irisin miti-gates endothelial barrier dysfunction and microvascular leakage-related diseases JJ.JCI Insight,2020,5（13):e 136 2 7 7.16 Zheng G,Li H,Zhang T,et al.Irisin protects macrophagesfrom oxidized low density lipoprotein-induced apoptosis by in-hibiting the endoplasmic reticulum stress pathway J.Saudi JBiol Sci，2 0 18，2 5(5):8 49-8 57.17 Mazur-Bialy AI,Pochec E,Zarawski M.Anti-Inflamma-tory Properties of Irisin,Mediator of Physical Activity,AreConnected with TLR4/MyD88 Signaling Pathway ActivationJJ.IntJMol Sci，2 0 17，18（4):7 0 1.18 Song H,Xu J,Lv N,et al.Irisin reverses platelet derivedgrowth factor-BB-induced vascular smooth muscle cells phe-notype modulation through STAT3 signaling pathway JJ.Bio-chem Biophys Res Commun,2016,479（2):139-145.19 Zhou B,Qiu Y,Wu N,et al.FNDC5 Attenuates OxidativeStress and NLRP3 Inflammasome Activation in VascularSmooth Muscle Cells via Activating the AMPK-SIRT1 SignalPathway J.Oxid Med Cell Longev,2020,2020:6384803.20 Zang YH,Chen D,Zhou B,et al.FNDC5 inhibits foamcell formation and monocyte adhesion in vascular smooth musclecells via suppressing NFkB-mediated NLRP3 upregulation JJ.Vascul Pharmacol,2019,121:106579.21 Moscoso I,Cebro-Marquez M,Rodriguez-Manero M,etal.FNDC5/Irisin counteracts lipotoxic-induced apoptosis inhypoxic H9c2 cells J.J Mol Endocrinol,2019,63（2):151-159.22 Ho MY,Wen MS,Yeh JK,et al.Excessive irisin increasesoxidative stress and apoptosis in murine heart J.BiochemBiophys Res Commun,2018,503（4):2 493-2 498.心血管康复医学杂志2 0 2 3年8 月第32 卷第4期ChinJCardiovascRehabilMed，A u g u s t2 0 2 3，V o l.32 No.423J Wang H,ZhaoYT,Zhang S,et al.Irisin plays a pivotalrole to protect the heart against ischemia and reperfusion injuryJJ.JC e ll Ph y s i o l,2 0 17，2 32（12)：37 7 5-37 8 5.24 Fan J,Zhu Q,Wu Z,et al.Protective effects of irisin onhypoxia-reoxygenation injury in hyperglycemia-treated car-diomyocytes:Role of AMPK pathway and mitochondrial pro-tectionJ.JCell Physiol,2020,235（2):116 5-117 4.25 Liao Q,Qu S,Tang LX,et al.Irisin exerts a therapeuticeffect against myocardial infarction via promoting angiogenesisJ.ActaPharmacol Sin，2 0 19,40 (10):1314-132 1.26 Zhao YT,Wang J,Yano N,et al.Irisin promotes cardiacprogenitor cell-induced myocardial repair and functional im-provement in infarcted heart J.J Cell Physiol,2019,234(2):1671-1681.27 Deng J,Zhang N,Wang Y,et al.FNDC5/irisin improvesthe therapeutic efficacy of bone marrow-derived mesenchymalstem cells for myocardial infarction JJ.Stem Cell Res Ther,2020,11(1)：2 2 8.28 Deng J,Zhang N,Chen F,et al.Irisin ameliorates high glu-cose-induced cardiomyocytes injury via AMPK/mTOR signalpathwayJJ.Cell Biol Int，2 0 2 0,44(11):2 315-2 32 5.29 Liu X,Mujahid H,Rong B,et al.Irisin inhibits high glu-cose-induced endothelial-to-mesenchymal transition and ex-erts a dose-dependent bidirectional effect on diabetic cardio-myopathy J.J Cell Mol Med,2018,22(2):808-822.3o Li RL,Wu SS,Wu Y,et al.Irisin alleviates pressure over-load-induced cardiac hypertrophy by inducing protective auto-phagy via mTOR-independent activation of the AMPK-ULK1 pathway J.J Mol Cell Cardiol,2018,121:242-255.31 Yu Q,Kou W,Xu X,et al.FNDC5/Irisin inhibits patho-logical cardiac hypertrophy JJ.Clin Sci（Lo n d),2 0 19,133(5):611627.32J Chen RR,Fan XH,Chen G,et al.Irisin attenuates angio-tensin II-induced cardiac fibrosis via Nrf2 mediated inhibitionof ROS/TGF1/Smad2/3 signaling axis JJ.Chem Biol Inter-act,2019,302:11-21.33 Geng Z,Fan WY,Zhou B,et al.FNDC5 attenuates obesity-induced cardiac hypertrophy by inactivating JAK2/STAT3-associated inflammation and oxidative stress J.J TranslMed，2 0 19,17(1):10 7.34 Ouyang H,Li Q,Zhong J,et al.Combination of melatoninand irisin ameliorates lipopolysaccharide-induced cardiac dys-function through suppressing the Mstl-JNK pathways JJ.JCell Physiol,2020,235(10):6647-6659.35 Zhang X,Hu C,Kong CY,et al.FNDC5 alleviates oxida-tive stress and cardiomyocyte apoptosis in doxorubicin-inducedcardiotoxicity via activating AKT J.Cell Death Differ,2020,27(2):540-555.（收稿日期：2 0 2 0-12 30)