Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Mechanism of miR-378a-3p enriched in M2 macrophage-derived extracellular vesicles in cardiomyocyte pyroptosis after MI

Hypertension Research volume 45, pages 650–664 (2022)Cite this article

Abstract

The development of novel therapies targeting cardiomyocyte pyroptosis is needed for myocardial infarction (MI). The current study sought to analyze the role and mechanism of M2 macrophage-derived extracellular vesicles (M2-EVs) in cardiomyocyte pyroptosis after MI. M2 macrophages were induced, and M2-EVs were separated and characterized. A mouse model of MI was successfully established, followed by an assessment of myocardial injury and cardiomyocyte pyroptosis. An in vitro cell model was established, followed by a comprehensive evaluation of cell viability and pyroptosis. The binding relationships of miR-378a-3p and ELAVL1 [human antigen R (HuR)], HuR, and NLR family pyrin domain containing 3 (NLRP3) were analyzed. A functional rescue experiment was designed to validate the role of HuR. After M2-EV treatment, the cardiac functions of mice with MI were restored, the myocardial injury was attenuated and cardiomyocyte pyroptosis was reduced. In vitro, M2-EVs suppressed hypoxic cell injury and pyroptosis. Mechanistically, M2-EVs delivered miR-378a-3p into cardiomyocytes to upregulate miR-378a-3p expression and inhibit ELAVL1 (HuR) expression and transport of HuR to the cytoplasm, thus destabilizing NLRP3 and inhibiting activation of the NLRP3/Caspase-1/GSDMD pathways. Overexpression of HuR inhibited the protective effect of M2-EVs in cardiomyocytes. Overall, our findings showed that M2-EV-enveloped miR-378a-3p inhibited HuR expression and HuR translocation to the cytoplasm to destabilize NLRP3 and block activation of the NLRP3/Caspase-1/GSDMD pathways, thereby attenuating cardiomyocyte pyroptosis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Reed GW, Rossi JE, Cannon CP. Acute myocardial infarction. Lancet. 2017;389:197–210.

    Article  PubMed  Google Scholar 

  2. Talman V, Ruskoaho H. Cardiac fibrosis in myocardial infarction-from repair and remodeling to regeneration. Cell Tissue Res. 2016;365:563–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. DeFilippis AP, Chapman AR, Mills NL, de Lemos JA, Arbab-Zadeh A, Newby LK, et al. Assessment and treatment of patients with Type 2 myocardial infarction and acute nonischemic myocardial injury. Circulation. 2019;140:1661–78.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Anderson JL, Morrow DA. Acute myocardial infarction. N. Engl J Med. 2017;376:2053–64.

    Article  CAS  PubMed  Google Scholar 

  5. Zhaolin Z, Guohua L, Shiyuan W, Zuo W. Role of pyroptosis in cardiovascular disease. Cell Prolif. 2019;52:e12563.

    Article  PubMed  Google Scholar 

  6. Ji N, Qi Z, Wang Y, Yang X, Yan Z, Li M, et al. Pyroptosis: a new regulating mechanism in cardiovascular disease. J Inflamm Res. 2021;14:2647–66.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Duncan SE, Gao S, Sarhene M, Coffie JW, Linhua D, Bao X, et al. Macrophage activities in myocardial infarction and heart failure. Cardiol Res Pr. 2020;2020:4375127.

    Google Scholar 

  8. Atri C, Guerfali FZ, Laouini D Role of human macrophage polarization in inflammation during infectious diseases. Int J Mol Sci. 2018;19:1801.

  9. Femmino S, Penna C, Margarita S, Comita S, Brizzi MF, Pagliaro P. Extracellular vesicles and cardiovascular system: biomarkers and cardioprotective effectors. Vasc Pharm. 2020;135:106790.

    Article  CAS  Google Scholar 

  10. Xu R, Zhang F, Chai R, Zhou W, Hu M, Liu B, et al. Exosomes derived from pro-inflammatory bone marrow-derived mesenchymal stem cells reduce inflammation and myocardial injury via mediating macrophage polarization. J Cell Mol Med. 2019;23:7617–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dai Y, Wang S, Chang S, Ren D, Shali S, Li C, et al. M2 macrophage-derived exosomes carry microRNA-148a to alleviate myocardial ischemia/reperfusion injury via inhibiting TXNIP and the TLR4/NF-kappaB/NLRP3 inflammasome signaling pathway. J Mol Cell Cardiol. 2020;142:65–79.

    Article  CAS  PubMed  Google Scholar 

  12. Zhu LP, Tian T, Wang JY, He JN, Chen T, Pan M, et al. Hypoxia-elicited mesenchymal stem cell-derived exosomes facilitates cardiac repair through miR-125b-mediated prevention of cell death in myocardial infarction. Theranostics. 2018;8:6163–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wei Z, Qiao S, Zhao J, Liu Y, Li Q, Wei Z, et al. miRNA-181a over-expression in mesenchymal stem cell-derived exosomes influenced inflammatory response after myocardial ischemia-reperfusion injury. Life Sci. 2019;232:116632.

    Article  CAS  PubMed  Google Scholar 

  14. Li Y, Yang R, Guo B, Zhang H, Zhang H, Liu S, et al. Exosomal miR-301 derived from mesenchymal stem cells protects myocardial infarction by inhibiting myocardial autophagy. Biochem Biophys Res Commun. 2019;514:323–8.

    Article  CAS  PubMed  Google Scholar 

  15. Zhao J, Chen F, Ma W, Zhang P. Suppression of long noncoding RNA NEAT1 attenuates hypoxia-induced cardiomyocytes injury by targeting miR-378a-3p. Gene. 2020;731:144324.

    Article  CAS  PubMed  Google Scholar 

  16. Chen T, Wang C, Yu H, Ding M, Zhang C, Lu X, et al. Increased urinary exosomal microRNAs in children with idiopathic nephrotic syndrome. EBioMedicine. 2019;39:552–61.

    Article  PubMed  Google Scholar 

  17. Tan J, Shen J, Zhu H, Gong Y, Zhu H, Li J, et al. miR-378a-3p inhibits ischemia/reperfusion-induced apoptosis in H9C2 cardiomyocytes by targeting TRIM55 via the DUSP1-JNK1/2 signaling pathway. Aging. 2020;12:8939–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Schultz CW, Preet R, Dhir T, Dixon DA, Brody JR. Understanding and targeting the disease-related RNA binding protein human antigen R (HuR). Wiley Interdiscip Rev RNA. 2020;11:e1581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Krishnamurthy P, Lambers E, Verma S, Thorne T, Qin G, Losordo DW, et al. Myocardial knockdown of mRNA-stabilizing protein HuR attenuates post-MI inflammatory response and left ventricular dysfunction in IL-10-null mice. FASEB J. 2010;24:2484–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Liu Y, Wei W, Wang Y, Wan C, Bai Y, Sun X, et al. TNF-alpha/calreticulin dual signaling induced NLRP3 inflammasome activation associated with HuR nucleocytoplasmic shuttling in rheumatoid arthritis. Inflamm Res. 2019;68:597–611.

    Article  CAS  PubMed  Google Scholar 

  21. Meng L, Lin H, Zhang J, Lin N, Sun Z, Gao F, et al. Doxorubicin induces cardiomyocyte pyroptosis via the TINCR-mediated posttranscriptional stabilization of NLR family pyrin domain containing 3. J Mol Cell Cardiol. 2019;136:15–26.

    Article  CAS  PubMed  Google Scholar 

  22. In: Guide for the care and use of laboratory animals. edn. Edited by th. Washington (DC); 2011.

  23. Zajac E, Schweighofer B, Kupriyanova TA, Juncker-Jensen A, Minder P, Quigley JP, et al. Angiogenic capacity of M1- and M2-polarized macrophages is determined by the levels of TIMP-1 complexed with their secreted proMMP-9. Blood. 2013;122:4054–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bian S, Zhang L, Duan L, Wang X, Min Y, Yu H. Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. J Mol Med. 2014;92:387–97.

    Article  CAS  PubMed  Google Scholar 

  25. Sun L, Zhu W, Zhao P, Wang Q, Fan B, Zhu Y, et al. Long noncoding RNA UCA1 from hypoxia-conditioned hMSC-derived exosomes: a novel molecular target for cardioprotection through miR-873-5p/XIAP axis. Cell Death Dis. 2020;11:696.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Papoutsidakis N, Arkadopoulos N, Smyrniotis V, Tzanatos H, Kalimeris K, Nastos K, et al. Early myocardial injury is an integral component of experimental acute liver failure - a study in two porcine models. Arch Med Sci. 2011;7:217–23.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Gokalp O, Eygi B, Gokalp G, Kiray M, Besir Y, Iscan S, et al. Which distant organ is most affected by lower extremity ischemia-reperfusion? Ann Vasc Surg. 2020;65:271–81.

    Article  PubMed  Google Scholar 

  28. Liu J, Jiang M, Deng S, Lu J, Huang H, Zhang Y, et al. miR-93-5p-containing exosomes treatment attenuates acute myocardial infarction-induced myocardial damage. Mol Ther Nucleic Acids. 2018;11:103–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhao TT, Yang TL, Gong L, Wu P. Isorhamnetin protects against hypoxia/reoxygenation-induced injure by attenuating apoptosis and oxidative stress in H9c2 cardiomyocytes. Gene. 2018;666:92–99.

    Article  CAS  PubMed  Google Scholar 

  30. Miranda KC, Huynh T, Tay Y, Ang YS, Tam WL, Thomson AM, et al. A pattern-based method for the identification of MicroRNA binding sites and their corresponding heteroduplexes. Cell. 2006;126:1203–17.

    Article  CAS  PubMed  Google Scholar 

  31. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402–8.

    Article  CAS  PubMed  Google Scholar 

  32. Wang Q, Wu J, Zeng Y, Chen K, Wang C, Yang S, et al. Pyroptosis: a pro-inflammatory type of cell death in cardiovascular disease. Clin Chim Acta. 2020;510:62–72.

    Article  CAS  PubMed  Google Scholar 

  33. Wang X, Fan L, Yin H, Zhou Y, Tang X, Fei X, et al. Protective effect of Aster tataricus extract on NLRP3-mediated pyroptosis of bladder urothelial cells. J Cell Mol Med. 2020;24:13336–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Moghaddam AS, Afshari JT, Esmaeili SA, Saburi E, Joneidi Z, Momtazi-Borojeni AA. Cardioprotective microRNAs: lessons from stem cell-derived exosomal microRNAs to treat cardiovascular disease. Atherosclerosis. 2019;285:1–9.

    Article  CAS  PubMed  Google Scholar 

  35. Krishnamurthy P, Rajasingh J, Lambers E, Qin G, Losordo DW, Kishore R. IL-10 inhibits inflammation and attenuates left ventricular remodeling after myocardial infarction via activation of STAT3 and suppression of HuR. Circ Res. 2009;104:e9–18.

    Article  CAS  PubMed  Google Scholar 

  36. Lei Q, Yi T, Chen C. NF-kappaB-Gasdermin D (GSDMD) axis couples oxidative stress and NACHT, LRR and PYD domains-containing Protein 3 (NLRP3) inflammasome-mediated cardiomyocyte pyroptosis following myocardial infarction. Med Sci Monit. 2018;24:6044–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhao L, Wang L, Zhang D, Chen Y, Jin F. Puerarin alleviates coronary heart disease via suppressing inflammation in a rat model. Gene. 2021;771:145354.

    Article  CAS  PubMed  Google Scholar 

  38. Juan CX, Mao Y, Cao Q, Chen Y, Zhou LB, Li S, et al. Exosome-mediated pyroptosis of miR-93-TXNIP-NLRP3 leads to functional difference between M1 and M2 macrophages in sepsis-induced acute kidney injury. J Cell Mol Med. 2021;25:4786–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Li Y, Jiang J, Liu W, Wang H, Zhao L, Liu S, et al. microRNA-378 promotes autophagy and inhibits apoptosis in skeletal muscle. Proc Natl Acad Sci USA. 2018;115:E10849–E10858.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hong L, Yu T, Xu H, Hou N, Cheng Q, Lai L, et al. Down-regulation of miR-378a-3p induces decidual cell apoptosis: a possible mechanism for early pregnancy loss. Hum Reprod. 2018;33:11–22.

    Article  CAS  PubMed  Google Scholar 

  41. Gu L, Wang H, Wang J, Guo Y, Tang Y, Mao Y, et al. Reconstitution of HuR-inhibited CUGBP1 expression protects cardiomyocytes from acute myocardial infarction-induced injury. Antioxid Redox Signal. 2017;27:1013–26.

    Article  CAS  PubMed  Google Scholar 

  42. Zhang Q, Huang XM, Liao JX, Dong YK, Zhu JL, He CC, et al. LncRNA HOTAIR promotes neuronal damage through facilitating NLRP3 mediated-pyroptosis activation in Parkinson’s disease via regulation of miR-326/ELAVL1 Axis. Cell Mol Neurobiol. 2020;41:1773–86.

  43. Jeyabal P, Thandavarayan RA, Joladarashi D, Suresh Babu S, Krishnamurthy S, Bhimaraj A, et al. MicroRNA-9 inhibits hyperglycemia-induced pyroptosis in human ventricular cardiomyocytes by targeting ELAVL1. Biochem Biophys Res Commun. 2016;471:423–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Li X, Zeng L, Cao C, Lu C, Lian W, Han J, et al. Long noncoding RNA MALAT1 regulates renal tubular epithelial pyroptosis by modulated miR-23c targeting of ELAVL1 in diabetic nephropathy. Exp Cell Res. 2017;350:327–35.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an City, Shaanxi Province, 710061, China

    Wei Yuan, Xiao Liang & Yingying Liu

  2. Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an City, Shaanxi Province, 710061, China

    Haichen Wang

Authors
  1. Wei Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiao Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yingying Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Haichen Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Haichen Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yuan, W., Liang, X., Liu, Y. et al. Mechanism of miR-378a-3p enriched in M2 macrophage-derived extracellular vesicles in cardiomyocyte pyroptosis after MI. Hypertens Res 45, 650–664 (2022). https://doi.org/10.1038/s41440-022-00851-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41440-022-00851-1

Keywords

This article is cited by

Search

Advanced search

Quick links