Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 2.1 (5-Year IF – 2.0)
Journal Citation Indicator (JCI) (2023) – 0.4
Scopus CiteScore – 3.7 (CiteScore Tracker 3.3)
Index Copernicus  – 161.11; MNiSW – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

Download original text (EN)

Advances in Clinical and Experimental Medicine

2020, vol. 29, nr 7, July, p. 803–812

doi: 10.17219/acem/121926

Publication type: original article

Language: English

License: Creative Commons Attribution 3.0 Unported (CC BY 3.0)

Download citation:

  • BIBTEX (JabRef, Mendeley)
  • RIS (Papers, Reference Manager, RefWorks, Zotero)

Effects of miR-124-3p regulation of the p38MAPK signaling pathway via MEKK3 on apoptosis and proliferation of macrophages in mice with coronary atherosclerosis

Chuannan Zhai1,2,A,B,C,D,E, Hongliang Cong1,2,E,F, Kai Hou1,2,A,B,C, Yuecheng Hu2,A,B, Jingxia Zhang2,A,B, Yingyi Zhang2,A,B, Ying Zhang2,A,B, Hong Zhang2,A,B

1 School of Medicine, Nankai University, Tianjin, China

2 Department of Cardiology, Tianjin Chest Hospital, China


Background. Atherosclerosis (AS) is the main cause of myocardial infarction and stroke. Macrophage apoptosis in the early stages can attenuate lesions, while in the late stage it is associated with AS plaque rupture.
Objectives. To explore the effects of miR-124-3p regulation of the p38MAPK signaling pathway via the MEKK3 gene on the apoptosis and proliferation of macrophages in mice with coronary AS.
Material and Methods. Fifty male apolipoprotein E (ApoE) −/− mice were equally assigned to a normal group and a coronary AS group. In the AS group, the mice were given a high-fat diet to establish a coronary AS model. The macrophages of the mice were isolated for culture and divided into 7 groups: normal, negative control (NC), control, miR-124-3p mimic, miR-124-3p inhibitor, si-MEKK3, and miR-124-3p inhibitor+si-MEKK3.
Results. Compared with the normal group, the AS group had lower expression levels of miR-124-3p and higher expression levels of MEKK3 and p-p38MAPK in the coronary artery tissue and peritoneal macrophages (all p < 0.050). We found that miR-124-3p could negatively regulate MEKK3 expression. Compared with the control group, the miR-124-3p mimic group and si-MEKK3 group had greater cell apoptosis rates and Bax levels, weaker cell proliferation and invasion abilities, slower cell cycle progression, and lower PCNA and Bcl-2 levels (all p < 0.050). This trend was also displayed in the miR-124-3p inhibitor+si-MEKK3 group when compared with the miR-124-3p inhibitor group, and in the si-MEKK3 group when compared with the miR-124-3p inhibitor+si-MEKK3 group (all p < 0.050).
Conclusion. miR-124-3p overexpression can downregulate MEKK3 expression and inhibit the expression of the p38MAPK signaling pathway, thereby inhibiting macrophage proliferation and promoting macrophage apoptosis in mice with coronary AS.

Key words

MiR-124-3p, macrophage, coronary atherosclerosis

References (30)

  1. Babaev VR, Huang J, Ding L, Zhang Y, May JM, Linton MF. Loss of rictor in monocyte/macrophages suppresses their proliferation and viability reducing atherosclerosis in LDLR null mice. Front Immunol. 2018;9:215.
  2. Kruth HS. Fluid-phase pinocytosis of LDL by macrophages: A novel target to reduce macrophage cholesterol accumulation in atherosclerotic lesions. Curr Pharm Des. 2013;19(33):5865–5872.
  3. McCurdy S, Baumer Y, Toulmin E, Lee BH, Boisvert WA. Macrophage-specific expression of IL-37 in hyperlipidemic mice attenuates athero­sclerosis. J Immunol. 2017;199(10):3604–3613.
  4. Xiao Y, He M, Liang X, et al. Pu-erh tea ameliorates atherosclerosis associated with promoting macrophage apoptosis by reducing NF-kappaB activation in ApoE knockout mice. Oxid Med Cell Longev. 2018;2018:3197829.
  5. Gonzalez L, Qian AS, Tahir U, Yu P, Trigatti BL. Sphingosine-1-phosphate receptor 1, expressed in myeloid cells, slows diet-induced atherosclerosis and protects against macrophage apoptosis in Ldlr KO mice. Int J Mol Sci. 2017;18(12):2721.
  6. Zhang YL, Li XB, Hou YX, Fang NZ, You JC, Zhou QH. The lncRNA XIST exhibits oncogenic properties via regulation of miR-449a and Bcl-2 in human non-small cell lung cancer. Acta Pharmacol Sin. 2017;38(3):371–381 [Erratum in: The lncRNA XIST exhibits oncogenic properties via regulation of miR-449a and Bcl-2 in human non-small cell lung cancer. Acta Pharmacol Sin. 2017;38(3):443].
  7. O’Connell RM, Rao DS, Chaudhuri AA, Baltimore D. Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol. 2010;10(2):111–122.
  8. Song K, Li L, Sun G, Wei Y. MicroRNA-381 regulates the occurrence and immune responses of coronary atherosclerosis via cyclooxygenase-2. Exp Ther Med. 2018;15(5):4557–4563.
  9. Ahmadi R, Heidarian E, Fadaei R, Moradi N, Malek M, Fallah S. miR-342-5p expression levels in coronary artery disease patients and its association with inflammatory cytokines. Clin Lab. 2018;64(4):603–609.
  10. Wang X, Lian Y, Wen X, et al. Expression of miR-126 and its potential function in coronary artery disease. Afr Health Sci. 2017;17(2):474–480.
  11. Zhao L, Jiao Y, Yang AN, et al. The effect of miR-124 on homocysteine-induced atherosclerosis via promoter region DNA methylation in ApoE(−/−) mice [in Chinese]. Sheng Li Xue Bao. 2015;67(2):207–213.
  12. Yang J, Lin Y, Guo Z, et al. The essential role of MEKK3 in TNF-induced NF-kappaB activation. Nat Immunol. 2001;2(7):620–624.
  13. Padda R, Wamsley-Davis A, Gustin MC, Ross R, Yu C, Sheikh-Hamad D. MEKK3-mediated signaling to p38 kinase and TonE in hypertonically stressed kidney cells. Am J Physiol Renal Physiol. 2006;291(4):F874–F881.
  14. Feng H, Cao J, Zhang G, Wang Y. Kaempferol attenuates cardiac hyper­trophy via regulation of ASK1/MAPK signaling pathway and oxidative stress. Planta Med. 2017;83(10):837–845.
  15. Ren R, Chen SD, Fan J, Zhang G, Li JB. miRNA-138 regulates MLK3/JNK/MAPK pathway to protect BV-2 cells from H2O2-induced apoptosis. Bratisl Lek Listy. 2018;119(5):284–288.
  16. Li Q, Park K, Xia Y, et al. Regulation of macrophage apoptosis and atherosclerosis by lipid-induced PKCdelta isoform activation. Circ Res. 2017;121(10):1153–1167.
  17. van Diepen JA, Berbee JF, Havekes LM, Rensen PC. Interactions between inflammation and lipid metabolism: Relevance for efficacy of anti-inflammatory drugs in the treatment of atherosclerosis. Atherosclerosis. 2013;228(2):306–315.
  18. Tabas I, Bornfeldt KE. Macrophage phenotype and function in different stages of atherosclerosis. Circ Res. 2016;118(4):653–667.
  19. Zhang Q, Lenardo MJ, Baltimore D. 30 years of NF-kappaB: A blossoming of relevance to human pathobiology. Cell. 2017;168(1–2):37–57.
  20. Liu Z, Gan L, Xu Y, et al. Melatonin alleviates inflammasome-induced pyroptosis through inhibiting NF-kappaB/GSDMD signal in mice adipose tissue. J Pineal Res. 2017;63(1). doi:10.1111/jpi.12414
  21. Dong RF, Zhang B, Tai LW, Liu HM, Shi FK, Liu NN. The neuroprotective role of miR-124-3p in a 6-hydroxydopamine-induced cell model of Parkinson’s disease via the regulation of ANAX5. J Cell Biochem. 2018;119(1):269–277.
  22. de Ronde MWJ, Kok MGM, Moerland PD, et al. High miR-124-3p expression identifies smoking individuals susceptible to atherosclerosis. Atherosclerosis. 2017;263:377–384.
  23. Geng L, Liu W, Chen Y. miR-124-3p attenuates MPP(+)-induced neuronal injury by targeting STAT3 in SH-SY5Y cells. Exp Biol Med (Maywood). 2017;242(18):1757–1764.
  24. Fan X, Wang C, Shi P, et al. Platelet MEKK3 regulates arterial thrombosis and myocardial infarct expansion in mice. Blood Adv. 2018;2(12):1439–1448.
  25. Ding SK, Wang LX, Guo LS, et al. Syringic acid inhibits apoptosis pathways via downregulation of p38MAPK and JNK signaling pathways in H9c2 cardiomyocytes following hypoxia/reoxygenation injury. Mol Med Rep. 2017;16(2):2290–2294.
  26. He H, Chang R, Zhang T, Yang C, Kong Z. ATM mediates DAB2IP-deficient bladder cancer cell resistance to ionizing radiation through the p38MAPK and NF-kappaB signaling pathway. Mol Med Rep. 2017;16(2):1216–1222.
  27. Menon MB, Gropengiesser J, Fischer J, et al. p38(MAPK)/MK2-dependent phosphorylation controls cytotoxic RIPK1 signalling in inflammation and infection. Nat Cell Biol. 2017;19(10):1248–1259.
  28. Cai Y, Li W, Tu H, et al. Curcumolide reduces diabetic retinal vascular leukostasis and leakage partly via inhibition of the p38MAPK/NF-kappa B signaling. Bioorg Med Chem Lett. 2017;27(8):1835–1839.
  29. Xu J, Tang S, Yin B, Sun J, Bao E. Co-enzyme Q10 upregulates Hsp70 and protects chicken primary myocardial cells under in vitro heat stress via PKC/MAPK. Mol Cell Biochem. 2018;449(1–2):195–206.
  30. Cui M, Wang J, Li Q, Zhang J, Jia J, Zhan X. Long non-coding RNA HOXA11-AS functions as a competing endogenous RNA to regulate ROCK1 expression by sponging miR-124-3p in osteosarcoma. Biomed Pharmacother. 2017;92:437–444.