NLRP3炎症小体与心房颤动的研究进展
|
摘要
心房颤动(AF)是临床最常见的快速性心律失常,其发生机制尚未完全阐明,而炎症反应增强常与AF的发生发展相关。核苷酸结合寡聚化结构域受体蛋白3(NLRP3)作为近年研究最为广泛最具特征性的炎症小体,参与诸多非感染性炎性反应。有证据显示其与心房重构、心肌纤维化密切相关,以此入手可为阐明AF的上游机制提供新的理论基础和研究靶点。本文简述了NLRP3的特性及信号传导途径,从基础和临床研究两方面总结了NLRP3与AF的相关性,并对未来NLRP3拮抗剂的应用作出了展望。
Atrial fibrillation(AF) is the most common tachyarrhythmia in clinic, but its mechanism has not been fully elucidated, and the increased inflammatory response is often associated with the occurrence and development of AF. As the most widely studied and characteristic inflammatory body in recent years, nucleotide-binding oligomerization domain-like receptor protein3(NLRP3) inflammasome participates in many non-infectious inflammatory reactions, while more evidences show that NLRP3 is closely related to atrial remodeling and myocardial fibrosis, which may provide a new theoretical basis and research target for the upstream mechanisms of AF. In this paper, the characteristics and signal transduction pathways of NLRP3 are briefly described, the correlation between NLRP3 and AF is summarized from both basic and clinical studies,and the future application of NLRP3 antagonist is prospected.
Atrial fibrillation(AF) is the most common tachyarrhythmia in clinic, but its mechanism has not been fully elucidated, and the increased inflammatory response is often associated with the occurrence and development of AF. As the most widely studied and characteristic inflammatory body in recent years, nucleotide-binding oligomerization domain-like receptor protein3(NLRP3) inflammasome participates in many non-infectious inflammatory reactions, while more evidences show that NLRP3 is closely related to atrial remodeling and myocardial fibrosis, which may provide a new theoretical basis and research target for the upstream mechanisms of AF. In this paper, the characteristics and signal transduction pathways of NLRP3 are briefly described, the correlation between NLRP3 and AF is summarized from both basic and clinical studies,and the future application of NLRP3 antagonist is prospected.
引文
[1]Andreadis EA,Geladari CV.Hypertension and atrial fibrillation:a bench to bedside perspective[J].Front Biosci,2018,10:276-284.doi:10.2741/s515.
[2]Korantzopoulos P,Letsas KP,Tse G,et al.Inflammation and atrial fibrillation:a comprehensive review[J].J Arrhythm,2018,34(4):394-401.doi:10.1002/joa3.12077.
[3]Liu C,Liu R,Fu H,et al.Pioglitazone attenuates atrial remodeling and vulnerability to atrial fibrillation in alloxan-induced diabetic rabbits[J].Cardiovasc Ther,2017,35(5):e12284.doi:10.1111/1755-5922.12284.
[4]Martinon F,Burns K,Tschopp J.The inflammasome:a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta[J].Mol Cell,2002,10:417-426.doi:10.1016/S1097-2765(02)00599-3.
[5]Grebe A,Hoss F,Latz E.NLRP3 inflammasome and the IL-1pathway in atherosclerosis[J].Circ Res,2018,122(12):1722-1740.doi:10.1161/CIRCRESAHA.118.311362.
[6]Kayagaki N,Stowe IB,Lee BL,et al.Caspase-11 cleaves gasdermin D for non-canonical inflammasome signaling[J].Nature,2015,526(7575):666-671.doi:10.1038/nature15541.
[7]Chen W,Zhao M,Zhao S,et al.Activation of the TXNIP/NLRP3inflammasome pathway contributes to inflammation in diabetic retinopathy:a novel inhibitory effect of minocycline[J].Inflamm Res,2017,66(2):157.doi:10.1007/s00011-016-1002-6.
[8]Liu N,Su H,Zhang Y,et al.Cholecalciterol cholesterol emulsion attenuates experimental autoimmune myocarditis in mice via inhibition of the pyroptosis signaling pathway[J].Biochem Bioph Res Commun,2017,493(1):422-428.doi:10.1016/j.bbrc.2017.09.006.
[9]Jeyabal P,Thandavarayan RA,Joladarashi D,et al.MicroRNA-9inhibits hyperglycemia induced cardiac pyroptosis in human ventricular cardiomyocytes by targeting ELAVL1[J].Biochem Bioph Res Commun,2016,471(4):423-429.doi:10.1016/j.bbrc.2016.02.065.
[10]Man SM,Kanneganti TD.Gasdermin D:The long-awaited executioner of pyroptosis[J].Cell Res,2015,25(11):1183-1184.doi:10.1038/cr.2015.124.
[11]Jo EK,Kim JK,Shin DM,et al.Molecular mechanisms regulating NLRP3 inflammasome activation[J].Cell Mol Immunol,2016,13(2):148-159.doi:10.1038/cmi.2015.95.
[12]Toldo S,Mezzaroma E,McGeough MD,et al.Independent roles of the priming and the triggering of the NLRP3 inflammasome in the heart[J].Cardiovasc Res,2015,105(2):203-212.doi:10.1093/cvr/cvu259.
[13]Hoyt LR,Randall MJ,Ather JL,et al.Mitochondrial ROS induced by chronic ethanol exposure promote hyper-activation of the NLRP3 inflammasome[J].Redox Biol,2017,12:883-896.doi:10.1016/j.redox.2017.04.020.
[14]谭红梅.NLRP3炎症小体与心血管疾病[J].中山大学学报,2017,38(2):215-221.Tan HM.Role of NLRP3 Inflammasome in Cardiovascular Diseases[J].Journal of Sun Yat-sen University,2017,38(2):215-221.doi:10.13471/j.cnki.j.sun.yatsen.univ(med.sci).2017.0035.
[15]Ren JD,Wu XB,Jiang R,et al.Molecular hydrogen inhibits lipopolysaccharide-triggered NLRP3 inflammasome activation in macrophages by targeting the mitochondrial reactive oxygen species[J].Biochim Biophys Acta,2016,1863(1):50-55.doi:10.1016/j.bbamcr.2015.10.012.
[16]Spindel ON,World C,Berk BC.Thioredoxin interacting protein:redox dependent and independent regulatory mechanisms[J].Antioxid Redox Sign,2012,16(6):587-596.doi:10.1089/ars.2011.4137.
[17]Scott L Jr,Li N,Dobrev D.Role of inflammatory signaling in atrial fibrillation[J].Int J Cardiol,2018 Oct 4.pii:S0167-5273(18)35864-9.doi:10.1016/j.ijcard.2018.10.020.[Epub ahead of print].
[18]刘长乐,刘瑞蒙,吴小寒,等.PPARγ-TLR4-TNF-α靶向路径在高糖血症致心肌炎症反应和氧化应激中的作用[J].中华危重病急救医学,2018,30(5):416-421.Liu CL,Liu RM,Wu XH,et al.Effects of peroxisome proliferator-activated receptorγ-toll-like receptor 4-tumor necrosis factor-αtargeted pathway on hyperglycemia induced myocardium inflammation and oxidative stress[J].Chinese Critical Care Medicine,2018,30(5):416-421.doi:10.3760/cma.j.issn.2095-4352.2018.05.005.
[19]许键,何燕,罗蓓蓓,等.NLRP3炎症小体与心房颤动的相关性研究[J].中国循环杂志,2017,32(1):72-76.Xu J,He Y,Luo BB,et al.Correlation Study Between NLRP3 inflammasome and Atrial Fibrillation[J].Chinese Circulation Journal,2017,32(1):72-76.doi:10.3969/j.issn.1000-3614.2017.01.017.
[20]Yao C,Veleva T,Scott L Jr,et al.Enhanced cardiomyocyte NLRP3inflammasome signaling promotes atrial fibrillation[J].Circulation,2018,138(20):2227-2242.doi:10.1161/CIRCULATIONAHA.118.035202.
[21]Chen G,Chelu MG,Dobrev D,et al.Cardiomyocyte inflammasome signaling in cardiomyopathies and atrial fibrillation:mechanisms and potential therapeutic implications[J].Front Physiol,2018,9:1115.doi:10.3389/fphys.2018.01115.
[22]Wan Y,Xu L,Wang Y,et al.Preventive effects of astragaloside IVand its active sapogenin cycloastragenol on cardiac fibrosis of mice by inhibiting the NLRP3 inflammasome[J].Eur J Pharmacol,2018,883:545.doi:10.1016/j.ejphar.2018.06.016.
[23]Shen H,Wang J,Min J,et al.Activation of TGF-β1/α-SMA/Col Iprofibrotic pathway in fibroblasts by galectin-3 contributes to atrial fibrosis in experimental models and patients[J].Cell Physiol Biochem,2018,47(2):851-863.doi:10.1159/000490077.
[24]Heijman J,Guichard JB,Dobrev D,et al.Translational challenges in atrial fibrillation[J].Circ Res,2018,122(5):752-773.doi:10.1161/CIRCRESAHA.117.311081.
[25]刘瑞蒙,刘长乐.Galectin-3与心房颤动的研究进展[J].天津医药,2017,45(12):1330-1333.Liu RM,Liu CL.Progress of galectin-3 and atrial fibrillation[J].Tianjin Med J,2017,45(12):1330-1333.doi:10.11958/20170636.
[2]Korantzopoulos P,Letsas KP,Tse G,et al.Inflammation and atrial fibrillation:a comprehensive review[J].J Arrhythm,2018,34(4):394-401.doi:10.1002/joa3.12077.
[3]Liu C,Liu R,Fu H,et al.Pioglitazone attenuates atrial remodeling and vulnerability to atrial fibrillation in alloxan-induced diabetic rabbits[J].Cardiovasc Ther,2017,35(5):e12284.doi:10.1111/1755-5922.12284.
[4]Martinon F,Burns K,Tschopp J.The inflammasome:a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta[J].Mol Cell,2002,10:417-426.doi:10.1016/S1097-2765(02)00599-3.
[5]Grebe A,Hoss F,Latz E.NLRP3 inflammasome and the IL-1pathway in atherosclerosis[J].Circ Res,2018,122(12):1722-1740.doi:10.1161/CIRCRESAHA.118.311362.
[6]Kayagaki N,Stowe IB,Lee BL,et al.Caspase-11 cleaves gasdermin D for non-canonical inflammasome signaling[J].Nature,2015,526(7575):666-671.doi:10.1038/nature15541.
[7]Chen W,Zhao M,Zhao S,et al.Activation of the TXNIP/NLRP3inflammasome pathway contributes to inflammation in diabetic retinopathy:a novel inhibitory effect of minocycline[J].Inflamm Res,2017,66(2):157.doi:10.1007/s00011-016-1002-6.
[8]Liu N,Su H,Zhang Y,et al.Cholecalciterol cholesterol emulsion attenuates experimental autoimmune myocarditis in mice via inhibition of the pyroptosis signaling pathway[J].Biochem Bioph Res Commun,2017,493(1):422-428.doi:10.1016/j.bbrc.2017.09.006.
[9]Jeyabal P,Thandavarayan RA,Joladarashi D,et al.MicroRNA-9inhibits hyperglycemia induced cardiac pyroptosis in human ventricular cardiomyocytes by targeting ELAVL1[J].Biochem Bioph Res Commun,2016,471(4):423-429.doi:10.1016/j.bbrc.2016.02.065.
[10]Man SM,Kanneganti TD.Gasdermin D:The long-awaited executioner of pyroptosis[J].Cell Res,2015,25(11):1183-1184.doi:10.1038/cr.2015.124.
[11]Jo EK,Kim JK,Shin DM,et al.Molecular mechanisms regulating NLRP3 inflammasome activation[J].Cell Mol Immunol,2016,13(2):148-159.doi:10.1038/cmi.2015.95.
[12]Toldo S,Mezzaroma E,McGeough MD,et al.Independent roles of the priming and the triggering of the NLRP3 inflammasome in the heart[J].Cardiovasc Res,2015,105(2):203-212.doi:10.1093/cvr/cvu259.
[13]Hoyt LR,Randall MJ,Ather JL,et al.Mitochondrial ROS induced by chronic ethanol exposure promote hyper-activation of the NLRP3 inflammasome[J].Redox Biol,2017,12:883-896.doi:10.1016/j.redox.2017.04.020.
[14]谭红梅.NLRP3炎症小体与心血管疾病[J].中山大学学报,2017,38(2):215-221.Tan HM.Role of NLRP3 Inflammasome in Cardiovascular Diseases[J].Journal of Sun Yat-sen University,2017,38(2):215-221.doi:10.13471/j.cnki.j.sun.yatsen.univ(med.sci).2017.0035.
[15]Ren JD,Wu XB,Jiang R,et al.Molecular hydrogen inhibits lipopolysaccharide-triggered NLRP3 inflammasome activation in macrophages by targeting the mitochondrial reactive oxygen species[J].Biochim Biophys Acta,2016,1863(1):50-55.doi:10.1016/j.bbamcr.2015.10.012.
[16]Spindel ON,World C,Berk BC.Thioredoxin interacting protein:redox dependent and independent regulatory mechanisms[J].Antioxid Redox Sign,2012,16(6):587-596.doi:10.1089/ars.2011.4137.
[17]Scott L Jr,Li N,Dobrev D.Role of inflammatory signaling in atrial fibrillation[J].Int J Cardiol,2018 Oct 4.pii:S0167-5273(18)35864-9.doi:10.1016/j.ijcard.2018.10.020.[Epub ahead of print].
[18]刘长乐,刘瑞蒙,吴小寒,等.PPARγ-TLR4-TNF-α靶向路径在高糖血症致心肌炎症反应和氧化应激中的作用[J].中华危重病急救医学,2018,30(5):416-421.Liu CL,Liu RM,Wu XH,et al.Effects of peroxisome proliferator-activated receptorγ-toll-like receptor 4-tumor necrosis factor-αtargeted pathway on hyperglycemia induced myocardium inflammation and oxidative stress[J].Chinese Critical Care Medicine,2018,30(5):416-421.doi:10.3760/cma.j.issn.2095-4352.2018.05.005.
[19]许键,何燕,罗蓓蓓,等.NLRP3炎症小体与心房颤动的相关性研究[J].中国循环杂志,2017,32(1):72-76.Xu J,He Y,Luo BB,et al.Correlation Study Between NLRP3 inflammasome and Atrial Fibrillation[J].Chinese Circulation Journal,2017,32(1):72-76.doi:10.3969/j.issn.1000-3614.2017.01.017.
[20]Yao C,Veleva T,Scott L Jr,et al.Enhanced cardiomyocyte NLRP3inflammasome signaling promotes atrial fibrillation[J].Circulation,2018,138(20):2227-2242.doi:10.1161/CIRCULATIONAHA.118.035202.
[21]Chen G,Chelu MG,Dobrev D,et al.Cardiomyocyte inflammasome signaling in cardiomyopathies and atrial fibrillation:mechanisms and potential therapeutic implications[J].Front Physiol,2018,9:1115.doi:10.3389/fphys.2018.01115.
[22]Wan Y,Xu L,Wang Y,et al.Preventive effects of astragaloside IVand its active sapogenin cycloastragenol on cardiac fibrosis of mice by inhibiting the NLRP3 inflammasome[J].Eur J Pharmacol,2018,883:545.doi:10.1016/j.ejphar.2018.06.016.
[23]Shen H,Wang J,Min J,et al.Activation of TGF-β1/α-SMA/Col Iprofibrotic pathway in fibroblasts by galectin-3 contributes to atrial fibrosis in experimental models and patients[J].Cell Physiol Biochem,2018,47(2):851-863.doi:10.1159/000490077.
[24]Heijman J,Guichard JB,Dobrev D,et al.Translational challenges in atrial fibrillation[J].Circ Res,2018,122(5):752-773.doi:10.1161/CIRCRESAHA.117.311081.
[25]刘瑞蒙,刘长乐.Galectin-3与心房颤动的研究进展[J].天津医药,2017,45(12):1330-1333.Liu RM,Liu CL.Progress of galectin-3 and atrial fibrillation[J].Tianjin Med J,2017,45(12):1330-1333.doi:10.11958/20170636.