Skip to main content
SpringerLink
Log in

Extracellular vesicles-mediated transfer of miR-208a/b exaggerate hypoxia/reoxygenation injury in cardiomyocytes by reducing QKI expression

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

In this study, we tested the hypothesis that extracellular vesicles (EVs)-mediated transfer of miR-208a/b can exacerbate apoptosis of cardiomyocytes (CMs) induced by hypoxia/reoxygenation (H/R) injury by reducing the expression of the RNA-binding protein Quaking (QKI). EVs were isolated from culture medium of hypoxic H9c2 cells (EVs-H). In in vitro H9c2 cell model, the EVs-H could be taken up by normoxic CMs and exacerbated cell apoptosis induced by H/R injury. In addition, miR-208a and miR-208b were enriched in EVs-H. Suppression of miR-208a and miR-208b loading significantly suppressed the detrimental effect of EVs-H on H/R injury in H9c2 cells. Inhibition of endogenous miR-208a and miR-208b restored QKI5 and QKI6 after H/R treatment. Dual-luciferase assay confirmed direct bindings between miR-208a/b and QKI 3′UTR. Functionally, QKI5 overexpression significantly suppressed H/R-induced CM apoptosis and suppressed the enhancing effect of EVs-H on CM apoptosis. Therefore, we infer that EVs-mediated transfer of miR-208a/b can exaggerate H/R injury in CMs by reducing QKI expression. This represents a previously unrecognized pathway of H/R injury in CMs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Minamino T (2012) Cardioprotection from ischemia/reperfusion injury: basic and translational research. Circ J 76:1074–1082

    Article  CAS  PubMed  Google Scholar 

  2. Chistiakov DA, Orekhov AN and Bobryshev YV (2016) Cardiac extracellular vesicles in normal and infarcted heart. Int J Mol Sci. doi:10.3390/ijms17010063

    PubMed  PubMed Central  Google Scholar 

  3. Fevrier B, Raposo G (2004) Exosomes: endosomal-derived vesicles shipping extracellular messages. Curr Opin Cell Biol 16:415–421. doi:10.1016/j.ceb.2004.06.003

    Article  CAS  PubMed  Google Scholar 

  4. Malik ZA, Kott KS, Poe AJ, Kuo T, Chen L, Ferrara KW, Knowlton AA (2013) Cardiac myocyte exosomes: stability, HSP60, and proteomics. Am J Physiol Heart Circ Physiol 304:H954–H965. doi:10.1152/ajpheart.00835.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bang C, Batkai S, Dangwal S, Gupta SK, Foinquinos A, Holzmann A, Just A, Remke J, Zimmer K, Zeug A, Ponimaskin E, Schmiedl A, Yin X, Mayr M, Halder R, Fischer A, Engelhardt S, Wei Y, Schober A, Fiedler J, Thum T (2014) Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J Clin Invest 124:2136–2146. doi:10.1172/JCI70577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Emanueli C, Shearn AI, Angelini GD, Sahoo S (2015) Exosomes and exosomal miRNAs in cardiovascular protection and repair. Vascul Pharmacol 71:24–30. doi:10.1016/j.vph.2015.02.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cervio E, Barile L, Moccetti T and Vassalli G (2015) Exosomes for intramyocardial intercellular communication. Stem Cells Int 2015:482171. doi:10.1155/2015/482171

    Article  PubMed  PubMed Central  Google Scholar 

  8. Yang Y, Li Y, Chen X, Cheng X, Liao Y, Yu X (2016) Exosomal transfer of miR-30a between cardiomyocytes regulates autophagy after hypoxia. J Mol Med 94:711–724. doi:10.1007/s00109-016-1387-2

    Article  CAS  PubMed  Google Scholar 

  9. Gupta S, Knowlton AA (2007) HSP60 trafficking in adult cardiac myocytes: role of the exosomal pathway. Am J Physiol Heart Circ Physiol 292:H3052–H3056. doi:10.1152/ajpheart.01355.2006

    Article  CAS  PubMed  Google Scholar 

  10. Liu X, Meng H, Jiang C, Yang S, Cui F, Yang P (2016) Differential microRNA expression and regulation in the rat model of post-infarction heart failure. PLoS ONE 11:e0160920. doi:10.1371/journal.pone.0160920

    Article  PubMed  PubMed Central  Google Scholar 

  11. Shyu KG, Wang BW, Wu GJ, Lin CM, Chang H (2013) Mechanical stretch via transforming growth factor-beta1 activates microRNA208a to regulate endoglin expression in cultured rat cardiac myoblasts. Eur J Heart Fail 15:36–45. doi:10.1093/eurjhf/hfs143

    Article  CAS  PubMed  Google Scholar 

  12. Shyu KG, Wang BW, Cheng WP, Lo HM (2015) MicroRNA-208a increases myocardial endoglin expression and myocardial fibrosis in acute myocardial infarction. Can J Cardiol 31:679–690. doi:10.1016/j.cjca.2014.12.026

    Article  PubMed  Google Scholar 

  13. Huang Y, Yang Y, He Y, Huang C, Meng X, Li J (2016) MicroRNA-208a potentiates angiotensin II-triggered cardiac myoblasts apoptosis via inhibiting nemo-like kinase (NLK). Curr Pharm Des 22:4868–4875

    Article  CAS  PubMed  Google Scholar 

  14. Bostjancic E, Jerse M, Glavac D, Zidar N (2015) miR-1, miR-133a/b, and miR-208a in human fetal hearts correlate to the apoptotic and proliferation markers. Exp Biol Med 240:211–219. doi:10.1177/1535370214546268

    Article  CAS  Google Scholar 

  15. Guo W, Jiang T, Lian C, Wang H, Zheng Q, Ma H (2014) QKI deficiency promotes FoxO1 mediated nitrosative stress and endoplasmic reticulum stress contributing to increased vulnerability to ischemic injury in diabetic heart. J Mol Cell Cardiol 75:131–140. doi:10.1016/j.yjmcc.2014.07.010

    Article  CAS  PubMed  Google Scholar 

  16. Guo W, Shi X, Liu A, Yang G, Yu F, Zheng Q, Wang Z, Allen DG, Lu Z (2011) RNA binding protein QKI inhibits the ischemia/reperfusion-induced apoptosis in neonatal cardiomyocytes. Cell Physiol Biochem 28:593–602. doi:10.1159/000335755

    Article  CAS  PubMed  Google Scholar 

  17. Kogure T, Patel T (2013) Isolation of extracellular nanovesicle microRNA from liver cancer cells in culture. Methods Mol Biol 1024:11–18. doi:10.1007/978-1-62703-453-1_2

    Article  CAS  PubMed  Google Scholar 

  18. Takahashi K, Yan IK, Wood J, Haga H, Patel T (2014) Involvement of extracellular vesicle long noncoding RNA (linc-VLDLR) in tumor cell responses to chemotherapy. Mol Cancer Res 12:1377–1387. doi:10.1158/1541-7786.MCR-13-0636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Dragovic RA, Gardiner C, Brooks AS, Tannetta DS, Ferguson DJ, Hole P, Carr B, Redman CW, Harris AL, Dobson PJ, Harrison P, Sargent IL (2011) Sizing and phenotyping of cellular vesicles using nanoparticle tracking analysis. Nanomedicine 7:780–788. doi:10.1016/j.nano.2011.04.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Garcia NA, Ontoria-Oviedo I, Gonzalez-King H, Diez-Juan A, Sepulveda P (2015) Glucose starvation in cardiomyocytes enhances exosome secretion and promotes angiogenesis in endothelial cells. PLoS ONE 10:e0138849. doi:10.1371/journal.pone.0138849

    Article  PubMed  PubMed Central  Google Scholar 

  21. Tony H, Meng K, Wu B, Yu A, Zeng Q, Yu K, Zhong Y (2015) MicroRNA-208a dysregulates apoptosis genes expression and promotes cardiomyocyte apoptosis during ischemia and its silencing improves cardiac function after myocardial infarction. Mediat Inflamm 2015:479123. doi:10.1155/2015/479123

    Article  Google Scholar 

  22. Corsten MF, Dennert R, Jochems S, Kuznetsova T, Devaux Y, Hofstra L, Wagner DR, Staessen JA, Heymans S, Schroen B (2010) Circulating MicroRNA-208b and MicroRNA-499 reflect myocardial damage in cardiovascular disease. Circ Cardiovasc Genet 3:499–506. doi:10.1161/CIRCGENETICS.110.957415

    Article  PubMed  Google Scholar 

  23. Bian C, Xu T, Zhu H, Pan D, Liu Y, Luo Y, Wu P, Li D (2015) Luteolin inhibits ischemia/reperfusion-induced myocardial injury in rats via downregulation of microRNA-208b-3p. PLoS ONE 10:e0144877. doi:10.1371/journal.pone.0144877

    Article  PubMed  PubMed Central  Google Scholar 

  24. Puthanveetil P, Wan A, Rodrigues B (2013) FoxO1 is crucial for sustaining cardiomyocyte metabolism and cell survival. Cardiovasc Res 97:393–403. doi:10.1093/cvr/cvs426

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The 7th Department of Internal Medicine (Department of Geriatric Cardiovascular and Cerebrovascular Diseases), Zaozhuang Hospital of Zaozhuang Mining Group, Zaozhuang, 277100, Shandong, China

    Feng Wang

  2. Department of Cardiology, Zoucheng People’s Hospital, Zoucheng, 273500, Shandong, China

    Yuxiang Yuan

  3. Department of Nursing, Binzhou People’s Hospital, Binzhou, 256600, Shandong, China

    Pirong Yang

  4. Department of Preventive Health Care, Weifang No.2 People’s Hospital, Weifang, 261000, Shandong, China

    Xia Li

Authors
  1. Feng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuxiang Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pirong Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xia Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xia Li.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, F., Yuan, Y., Yang, P. et al. Extracellular vesicles-mediated transfer of miR-208a/b exaggerate hypoxia/reoxygenation injury in cardiomyocytes by reducing QKI expression. Mol Cell Biochem 431, 187–195 (2017). https://doi.org/10.1007/s11010-017-2990-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-017-2990-4

Keywords

Search

Navigation