Journal of Shandong University (Health Sciences) ›› 2019, Vol. 57 ›› Issue (4): 9-14.doi: 10.6040/j.issn.1671-7554.0.2018.1344

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Effects of c-Jun N-terminal kinase regulated by CD40siRNA on the autophagy of cardiomyocytes in rats with autoimmune myocarditis

SUN Honglin1, HAN Bo1, WANG Jing1, GAO Ling2, ZHU Mei1, JIANG Diandong1, LÜ Jianli1   

  1. 1. Department of Pediatric Cardiology;
    2. Central Laboratory, Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong, China
  • Published:2022-09-27

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Abstract: Objective To investigate the effects of CD40siRNA regulated c-Jun N-terminal kinase(JNK)pathway on the autophagy of cardiomyocytes in experimental autoimmune myocarditis(EAM). Methods A total of 32 healthy male Lewis rats aged 6 to 8 weeks were randomly divided into the EAM group, EAM+CD40siRNA group, EAM+siRNA control group, and normal control group(NC group), with 8 rats in each group. The EAM models were established by injecting mixed porcine heart immunoglobulin(0.2 mL/rat)into the hind paw pad of rats in the first 3 groups on day 0 and day 7. Rats in the NC group were injected with 0.2 mL/rat of phosphate buffered saline(PBS). On day 7, rats in the EAM+CD40siRNA group were injected with 25 μL of CD40siRNA lentiviral vector in the tail vein, and rats in the EAM+siRNA control group were injected with 25 μL of LsiRNA lentiviral vector. The body weight of rats was measured every 3 days. All rats were sacrificed on day 21. Pathological changes of the myocardial tissues were observed 山 东 大 学 学 报 (医 学 版)57卷4期 -孙红林,等.CD40siRNA调控c-Jun氨基末端激酶对自身免疫性心肌炎大鼠心肌细胞自噬的影响 \=-with a light microscopy and pathological scores were calculated. The JNK was immunohistochemically stained. The autophagy-related protein Beclin1 and microtubule-associated protein light chain 3-Ⅱ/Ⅰ ratio(LC3-Ⅱ/Ⅰ)were detected with Western blotting. Results During the experiment, no rats died. The body mass of rats in the NC group increased faster than that in the EAM group(P<0.05). The EAM+CD40siRNA group had significantly lower pathological scores than the EAM group(P<0.001). The EAM+CD40siRNA group and NC group had significantly lower LC3-Ⅱ/Ⅰ and Beclin1 than the EAM group, and there was a positive correlation between JNK and LC3-Ⅱ(r=0.985, P<0.001). Conclusion The CD40siRNA can relieve the inflammation of EAM rats, possibly by downregulating the JNK pathway and inhibiting the autophagy of cardiomyocytes.

Key words: Autoimmune myocarditis, Autophagy, CD40-CD40 ligand, C-Jun N-terminal kinase, Microtubule-associated protein light chain 3-II/I

CLC Number: 

  • R725.4
[1] Kawai C. From myocarditis to cardiomyopathy: mechanisms of inflammation and cell death: learning from the past for the future[J]. Circulation, 1999, 99(8): 1091-1100.
[2] Kodama M, Matsumoto Y, Fujiwara M, et al. A novel experimental model of giant cell myocarditis induced in rats by immunization with cardiac myosin fraction[J]. Clin Immunol Immunopathol, 1990, 57(2): 250-262.
[3] Fuse K, Kodama M, Ito M, et al. Polarity of helper T cell subsets represents disease nature and clinical course of experimental autoimmune myocarditis in rats[J]. Clin Exp Immunol, 2003, 134(3): 403-408.
[4] Kodama M, Zhang S, Hanawa H, et al. Immunohistochemical characterization of infiltrating mononuclear cells in the rat heart with experimental autoimmune giant cell myocarditis[J]. Clin Exp Immunol, 1992, 90(2): 330-335.
[5] Vallerie SN, Hotamisligil GS. The role of JNK proteins in metabolism[J]. Sci Transl Med, 2010, 2(60): 60.
[6] Solinas G, Becattini B. JNK at the crossroad of obesity, insulin resistance, and cell stress response[J]. Mol Metab, 2017, 6(2): 174-184.
[7] Zhou YY, Li Y, Jiang WQ, et al. MAPK/JNK signalling: a potential autophagy regulation pathway[J]. Biosci Rep, 2015, 35(3): e00199. doi: 10.1042/BSR20140141.
[8] Bachmaier K, Toya S, Malik AB. Therapeutic administration of the chemokine CXCL1/KC abrogates autoimmune inflammatory heart disease[J]. PLoS One, 2014, 9(2): e89647. doi: 10.1371/journal.pone.0089647.
[9] Matsui Y, Inobe M, Okamoto H, et al. Blockade of T cell costimulatory signals using adenovirus vectors prevents both the induction and the progression of experimental autoimmune myocarditis[J]. J Mol Cell Cardiol, 2002, 34(3): 279-295.
[10] 杨文巍. CD40siRNA对自身免疫性心肌炎大鼠Th17细胞及IL-17与IL-23的作用[D]. 济南: 山东大学, 2013.
[11] 张荣军, 韩波, 高聆, 等. siRNA沉默CD40基因对实验性自身免疫性心肌炎大鼠的作用及 IL-22表达的影响[J]. 山东大学学报(医学版), 2015, 53(5): 36-40. ZHANG Rongjun, HAN Bo, GAO Ling, et al. Effects of CD40 knockdown by siRNA on rats with experimental autoimmune myocarditis and IL-22 expression[J]. Journal of Shandong University(Health Sciences), 2015, 53(5): 36-40.
[12] Cui Y, Jiang L, Shao Y, et al. Anti-alcohol liver disease effect of Gentianae macrophyllae extract through MAPK/JNK/p38 pathway[J]. J Pharm Pharmacol, 2019, 71(2): 240-250.
[13] Hommes DW, Peppelenbosch MP, van Deventer SJ.Mitogen activated protein(MAP)kinase signal transduction pathways and novel anti-inflammatory targets[J]. Gut, 2003, 52(1): 144-151.
[14] Zanotti S, Kumar A, Kumar A. Cytokine modulation in sepsis and septic shock[J]. Expert Opin Investig Drugs, 2002, 11(8): 1061-1075.
[15] Dai Q, Zhang D, Yu H, et al. Berberine Restricts Coxsackievirus B Type 3 Replication via Inhibition of c-Jun N-Terminal Kinase(JNK)and p38 MAPK Activation In Vitro[J]. Med Sci Monit, 2017, 23(25): 1448-1455.
[16] Johnson JC, Martinez O, Honko AN, et al. Pyridinyl imidazole inhibitors of p38 MAP kinase impair viral entry and reduce cytokine induction by Zaire ebolavirus in human dendritic cells[J]. Antiviral Res, 2014, 107: 102-109.doi: 10.1016/j.antiviral.2014.04.014.
[17] Kim SM, Park JH, Chung SK, et al. Coxsackievirus B3 infection induces cyr61 activation via JNK to mediate cell death[J]. J Virol, 2004, 78(24): 13479-13488.
[18] Kim EK, Choi EJ. Pathological roles of MAPK signaling pathways in human diseases[J]. Biochim Biophys Acta, 2010, 1802(4): 396-405.
[19] Cargnello M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases[J]. Microbiol Mol Biol Rev, 2011, 75(1): 50-83.
[20] Tan YQ, Zhang J, Zhou G. Autophagy and its implication in human oral diseases[J]. Autophagy, 2017, 13(2): 225-236.
[21] Wong J, Zhang J, Si X, et al. Autophagosome supports coxsackievirus B3 replication in host cells[J]. J Virol, 2008, 82(18): 9143-9153.
[22] Eskelinen EL. Maturation of autophagic vacuoles in Mammalian cells[J]. Autophagy, 2005, 1(1): 1-10.
[23] Klionsky DJ, Baehrecke EH, Brumell JH, et al. A comprehensive glossary of autophagy-related molecules and processes(2nd edition)[J]. Autophagy, 2011, 7(11): 1273-1294.
[24] Aoki H, Kang PM, Hampe J, et al. Direct activation of mitochondrial apoptosis machinery by c-Jun N-terminal kinase in adult cardiac myocytes[J]. J Biol Chem, 2002, 277(12): 10244-10250.
[25] Gao F, Yue TL, Shi DW. p38 MAPK inhibition reduces myocardial reperfusion injury via inhibition of endothelial adhesion molecule expression and blockade of PMN accumulation[J]. Cardiovasc Res, 2002, 53(2): 414-422.
[26] Jeong CW, Yoo KY, Lee SH, et al. Curcumin protects against regional myocardial ischemia/reperfusion injury through activation of RISK/GSK-3beta and inhibition of p38 MAPK and JNK[J]. J Cardiovasc Pharmacol Ther, 2012, 17(4): 387-394.
[27] Qi L, Xin Q, Wenjun J. Inhibition of iNOS protects cardiomyocytes against coxsackievirus B3-induced cell injury by suppressing autophagy[J]. Biomed Pharmacother, 2017, 91: 673-679. doi: 10.1016/j.biopha.2017.04.123.
[28] Reddy KB, Nabha SM, Atanaskova N. Role of MAP kinase in tumor progression and invasion[J]. Cancer Metastasis Rev, 2003, 22(4): 395-403.
[29] Xu YF, Liu M, Peng B, et al.Protective effects of SP600125 on renal ischemia-reperfusion injury in rats[J]. J Surg Res, 2011, 169(1): 77-84.
[30] Sarkar S, Rubinsztein DC. Huntingtons disease: degradation of mutant huntingtin by autophagy[J]. FEBS J, 2008, 275(17): 4263-4270.
[31] Wu ZZ, Zhang JJ, Gao CC, et al. Expression of autophagy related genes mTOR, Becline-1, LC3 and p62 in the peripheral blood mononuclear cells of systemic lupus erythematosus[J]. Am J Clin Exp Immunol, 2017, 6(1): 1-8.
[32] Zhai X, Bai B, Yu B, et al. Coxsackievirus B3 Induces Autophagic Response in Cardiac Myocytes in vivo[J]. Biochemistry(Mosc), 2015, 80(8): 1001-1009.
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