NLRP3炎性小体与糖尿病心肌病的研究进展

doi:10.3760/cma.j.issn.1007-1245.2023.16.001

摘要/Abstract

摘要：

糖尿病心肌病（DCM）是由糖尿病导致的特异性心脏病，独立于其他心血管疾病。关于DCM的发病机制尚不十分明确，研究发现，炎症在DCM的发生、发展过程中起到了重要作用。随着NLRs家族的发现，NLRP3炎性小体与DCM的研究越来越多。大量证据表明NLRP3能够介导促炎因子的释放和细胞焦亡，参与DCM的病理生理过程。本文就NLRP3炎性小体的基本知识、NLRP3与DCM的关系以及DCM中靶向NLRP3的治疗药物进行系统综述。

关键词:

糖尿病心肌病, 炎症, NLRP3炎性小体, 发病机制, 治疗, 进展

Abstract:

Diabetic cardiomyopathy (DCM) is a specific heart disease caused by diabetes, and is independent from other cardiovascular diseases. The pathogenesis of DCM is not very clear. Studies have found that inflammation plays an important role in the occurrence and development of DCM. With the discovery of NLRs family, more and more studies have been conducted on NLRP3 inflammasome and DCM. A large amount of evidence suggests that NLRP3 is involved in the pathophysiological process of DCM by mediating the release of pro-inflammatory factors and pyrodeath of cells. In this article, we systematically review the basic knowledge of NLRP3 inflammatories, the relationship between NLRP3 and DCM, and the therapeutic drugs targeting NLRP3 in DCM.

Key words:

Diabetic cardiomyopathy, Inflammation, NLRP3 inflammasome, Pathogenesis, Treatment, Progress

张翠刘振刘婧扬石新烨刘志强孙经武.

NLRP3炎性小体与糖尿病心肌病的研究进展 [J]. 国际医药卫生导报, 2023, 29(16): 2221-2225.

Zhang Cui, Liu Zhen, Liu Jingyang, Shi Xinye, Liu Zhiqiang, Sun Jingwu.

NLRP3 inflammasome and diabetic cardiomyopathy [J]. International Medicine and Health Guidance News, 2023, 29(16): 2221-2225.

参考文献

[1] Boudina S, Abel ED. Diabetic cardiomyopathy revisited[J]. Circulation, 2007, 115(25):3213-3223. DOI: 10.1161/CIRCULATIONAHA.
[2] Rubler S, Dlugash J, Yuceoglu YZ, et al. New type of cardiomyopathy associated with diabetic glomerulosclerosis[J]. Am J Cardiol, 1972, 30(6):595-602. DOI: 10.1016/0002-9149(72)90595-4.
[3] Murtaza G, Virk HUH, Khalid M, et al. Diabetic cardiomyopathy - a comprehensive updated review[J]. Prog Cardiovasc Dis, 2019,62(4):315-326. DOI: 10.1016/j.pcad.2019.03.003.
[4] Ahmed U, Khaliq S, Ahmad HU, et al. Pathogenesis of diabetic cardiomyopathy and role of miRNA[J]. Crit Rev Eukaryot Gene Expr, 2021,31(1):79-92. DOI: 10.1615/CritRevEukaryotGeneExpr.2021037533.
[5] Williams LJ, Nye BG, Wende AR. Diabetes-related cardiac dysfunction[J]. Endocrinol Metab (Seoul), 2017,32(2):171-179. DOI: 10.3803/EnM.2017.32.2.171.
[6] Rathinam VA, Fitzgerald KA. Inflammasome complexes: emerging mechanisms and effector functions[J]. Cell, 2016,165(4):792-800. DOI: 10.1016/j.cell.2016.03.046.
[7] Zahid A, Li B, Kombe AJK, et al. Pharmacological Inhibitors of the NLRP3 Inflammasome[J]. Front Immunol, 2019,10:2538. DOI: 10.3389/fimmu. 2019.02538.
[8] Man SM, Kanneganti TD. Regulation of inflammasome activation[J]. Immunol Rev, 2015,265(1):6-21. DOI: 10.1111/imr.12296.
[9] Zhen Y, Zhang H. NLRP3 inflammasome and inflammatory bowel disease[J]. Front Immunol, 2019,10:276. DOI: 10.3389/fimmu.2019.00276.
[10] Li Z, Guo J, Bi L. Role of the NLRP3 inflammasome in autoimmune diseases[J]. Biomed Pharmacother, 2020, 130:110542. DOI: 10.1016/j.biopha.2020.110542.
[11] Biasizzo M, Kopitar-Jerala N. Interplay between NLRP3 inflammasome and autophagy[J]. Front Immunol, 2020,11:591803. DOI: 10.3389/fimmu.2020.591803.
[12] Mezzaroma E, Abbate A, Toldo S. NLRP3 inflammasome inhibitors in cardiovascular diseases[J]. Molecules, 2021,26(4):976. DOI: 10.3390/molecules26040976.
[13] Bauernfeind FG, Horvath G, Stutz A, et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression[J]. J Immunol, 2009,183(2):787-791. DOI: 10.4049/jimmunol.0901363.
[14] Elliott EI, Sutterwala FS. Initiation and perpetuation of NLRP3 inflammasome activation and assembly[J]. Immunol Rev, 2015,265(1):35-52. DOI: 10.1111/imr.12286.
[15] Zhao C, Zhao W. NLRP3 Inflammasome-a key player in antiviral responses[J]. Front Immunol, 2020,11:211. DOI: 10.3389/fimmu.2020.00211.
[16] Luo B, Li B, Wang W, et al. NLRP3 gene silencing ameliorates diabetic cardiomyopathy in a type 2 diabetes rat model[J]. PLoS One, 2014,9(8):e104771. DOI: 10.1371/journal.pone.0104771.
[17] Zeng C, Wang R, Tan H. Role of pyroptosis in cardiovascular diseases and its therapeutic implications[J]. Int J Biol Sci, 2019,15(7):1345-1357. DOI: 10.7150/ijbs.33568.
[18] Qiu Z, He Y, Ming H, et al. Lipopolysaccharide (LPS) aggravates high glucose-and hypoxia/reoxygenation- induced injury through activating ROS-dependent NLRP3 inflammasome-mediated pyroptosis in H9C2 cardiomyocytes[J]. J Diabetes Res, 2019,2019:8151836. DOI: 10.1155/2019/8151836.
[19] Elmadbouh I, Singla DK. BMP-7 attenuates inflammation- induced pyroptosis and improves cardiac repair in diabetic cardiomyopathy[J]. Cells, 2021,10(10):2640. DOI: 10.3390/cells10102640.
[20] Xie Y, Huang Y, Ling X, et al. Chemerin/CMKLR1 axis promotes inflammation and pyroptosis by activating NLRP3 inflammasome in diabetic cardiomyopathy rat[J]. Front Physiol, 2020,11:381. DOI: 10.3389/fphys. 2020.00381.
[21] Kang LL, Zhang DM, Ma CH, et al. Cinnamaldehyde and allopurinol reduce fructose-induced cardiac inflammation and fibrosis by attenuating CD36-mediated TLR4/6-IRAK4/1 signaling to suppress NLRP3 inflammasome activation[J]. Sci Rep, 2016,6:27460. DOI: 10.1038/srep27460.
[22] Bracey NA, Gershkovich B, Chun J, et al. Mitochondrial NLRP3 protein induces reactive oxygen species to promote Smad protein signaling and fibrosis independent from the inflammasome[J]. J Biol Chem, 2014,289(28):19571-19584. DOI: 10.1074/jbc.M114.550624.
[23] Zhang X, Pan L, Yang K, et al. H3 Relaxin Protects Against Myocardial Injury in Experimental Diabetic Cardiomyopathy by Inhibiting Myocardial Apoptosis, Fibrosis and Inflammation[J]. Cell Physiol Biochem, 2017,43(4):1311-1324. DOI: 10.1159/000481843.
[24] Sivasankar D, George M, Sriram DK. Novel approaches in the treatment of diabetic cardiomyopathy[J]. Biomed Pharmacother, 2018,106:1039-1045. DOI: 10.1016/j.biopha.2018.07.051.
[25] Yang F, Qin Y, Wang Y, et al. Metformin inhibits the NLRP3 inflammasome via AMPK/mTOR-dependent effects in diabetic cardiomyopathy[J]. Int J Biol Sci, 2019,15(5):1010-1019. DOI: 10.7150/ijbs.29680.
[26] Ye Y, Bajaj M, Yang HC, et al. SGLT-2 Inhibition with Dapagliflozin reduces the activation of the Nlrp3/ASC Inflammasome and attenuates the development of diabetic cardiomyopathy in mice with type 2 diabetes. Further Augmentation of the effects with saxagliptin, a DPP4 inhibitor[J]. Cardiovasc Drugs Ther, 2017,31(2):119-132. DOI: 10.1007/s10557-017-6725-2.
[27] Xue M, Li T, Wang Y, et al. Empagliflozin prevents cardiomyopathy via sGC-cGMP-PKG pathway in type 2 diabetes mice[J]. Clin Sci (Lond), 2019,133(15):1705-1720. DOI: 10.1042/CS20190585.
[28] Che H, Wang Y, Li H, et al. Melatonin alleviates cardiac fibrosis via inhibiting lncRNA MALAT1/miR-141- mediated NLRP3 inflammasome and TGF-β1/Smads signaling in diabetic cardiomyopathy[J]. FASEB J, 2020,34(4):5282-5298. DOI: 10.1096/fj.201902692R.
[29] Luo B, Li B, Wang W, et al. Rosuvastatin alleviates diabetic cardiomyopathy by inhibiting NLRP3 inflammasome and MAPK pathways in a type 2 diabetes rat model[J]. Cardiovasc Drugs Ther, 2014,28(1):33-43. DOI: 10.1007/s10557-013-6498-1.
[30] Zhang H, Chen X, Zong B, et al. Gypenosides improve diabetic cardiomyopathy by inhibiting ROS-mediated NLRP3 inflammasome activation[J]. J Cell Mol Med, 2018,22(9):4437-4448. DOI: 10.1111/jcmm.13743.
[31] Yan M, Li L, Wang Q, et al. The Chinese herbal medicine Fufang Zhenzhu Tiaozhi protects against diabetic cardiomyopathy by alleviating cardiac lipotoxicity- induced oxidative stress and NLRP3-dependent inflammasome activation[J]. Biomed Pharmacother, 2022,148:112709. DOI: 10.1016/j.biopha. 2022.112709.
[32] Jiang C, Li D, Chen L, et al. Quercetin ameliorated cardiac injury via reducing inflammatory actions and the glycerophospholipid metabolism dysregulation in a diabetic cardiomyopathy mouse model[J]. Food Funct, 2022,13(14):7847-7856. DOI: 10.1039/d2fo00912a.
[33] Wen Y, Geng L, Zhou L, et al. Betulin alleviates on myocardial inflammation in diabetes mice via regulating Siti1/NLRP3/NF-κB pathway[J]. Int Immunopharmacol, 2020,85:106653. DOI: 10.1016/j.intimp.2020.106653.