Skip to main content
SpringerLink
Log in

Exosomal transfer of miR-30a between cardiomyocytes regulates autophagy after hypoxia

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Recent studies have indicated a protective role of physiological autophagy in ischemic heart disease. However, the underlying mechanisms of autophagy regulation after ischemia are poorly understood. Exosomes are nano-sized vesicles released from cells that play critical roles in mediating cell-to-cell communication through the transfer of microRNAs. In this study, we observed that miR-30a was highly enriched in exosomes from the serum of acute myocardial infarction (AMI) patients in vivo and culture medium of cardiomyocytes after hypoxic stimulation in vitro. We also found that hypoxia inducible factor (HIF)-1α regulates miR-30a, which efficiently transferred via exosomes between cardiomyocytes after hypoxia. Inhibition of miR-30a or release of exosomes increased the expression of the core autophagy regulators beclin-1, Atg12, and LC3II/LC3I, which contributed to maintaining the autophagic response in cardiomyocytes after hypoxia. Taken together, the present study showed that exosomes from hypoxic cardiomyocytes regulate autophagy by transferring miR-30a in a paracrine manner, which revealed a new pathway of autophagy regulation that might comprise a promising strategy to treat ischemic heart disease.

Key messages

  • miR-30a is highly enriched in exosomes from the serum of AMI patients.

  • Hypoxia induces miR-30a upregulation and enrichment into exosomes.

  • MiR-30a is efficiently transferred via exosomes between hypoxic cardiomyocytes.

  • Inhibition of exosome release contributes to maintaining of autophagy after hypoxia.

  • Inhibition of miR-30a augments autophagy after hypoxia.

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
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Kanamori H, Takemura G, Goto K et al (2011) The role of autophagy emerging in postinfarction cardiac remodelling. Cardiovasc Res 91:330–339

    Article  CAS  PubMed  Google Scholar 

  2. Shintani T, Klionsky DJ (2004) Autophagy in health and disease: a double-edged sword. Science 306:990–995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kanamori H, Takemura G, Goto K et al (2011) Autophagy limits acute myocardial infarction induced by permanent coronary artery occlusion. Am J Physiol Heart Circ Physiol 300:H2261–2271

    Article  CAS  PubMed  Google Scholar 

  4. Zhu H, Wu H, Li B et al (2009) Regulation of autophagy by a beclin 1-targeted microRNA, miR-30a, in cancer cells. Autophagy 5:816–823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Korkmaz G, le Sage C, Tekirdag KA et al (2012) miR-376b controls starvation and mTOR inhibition-related autophagy by targeting ATG4C and BECN1. Autophagy 8:165–176

    Article  CAS  PubMed  Google Scholar 

  6. Ucar A, Gupta SK, Fiedler J et al (2012) The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy. Nat Commun 3:1078

    Article  PubMed  PubMed Central  Google Scholar 

  7. Long G, Wang F, Duan Q et al (2012) Circulating miR-30a, miR-195 and let-7b associated with acute myocardial infarction. PLoS One 7:e50926

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Skog J, Würdinger T, van Rijn S et al (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10:1470–1476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Creemers EE, Tijsen AJ, Pinto YM (2012) Circulating microRNAs: novel biomarkers and extracellular communicators in cardiovascular disease? Circ Res 110:483–495

    Article  CAS  PubMed  Google Scholar 

  10. Thygesen K, Alpert JS, Jaffe AS et al (2012) Third universal definition of myocardial infarction. J Am Coll Cardiol 60:1581–1598

    Article  PubMed  Google Scholar 

  11. Dubovsky JA, Chappell DL, Harrington BK et al (2013) Lymphocyte cytosolic protein 1 is a chronic lymphocytic leukemia membrane-associated antigen critical to niche homing. Blood 122:3308–3316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Duisters RF, Tijsen AJ, Schroen B et al (2009) miR-133 and miR-30 regulate connective tissue growth factor: implications for a role of microRNAs in myocardial matrix remodeling. Circ Res 104:170–178

    Article  CAS  PubMed  Google Scholar 

  13. Pan W, Zhong Y, Cheng C et al (2013) MiR-30-regulated autophagy mediates angiotensin II-induced myocardial hypertrophy. PLoS One 8:e53950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wang P, Zhang N, Liang J et al (2015) Micro-RNA-30a regulates ischemia-induced cell death by targeting heat shock protein HSPA5 in primary cultured cortical neurons and mouse brain after stroke. J Neurosci Res. doi:10.1002/jnr.23637

    Google Scholar 

  15. Mitchell PS, Parkin RK, Kroh EM et al (2008) Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A 105:10513–10518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mittelbrunn M, Sánchez-Madrid F (2012) Intercellular communication: diverse structures for exchange of genetic information. Nat Rev Mol Cell Biol 13:328–335

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Vickers KC, Palmisano BT, Shoucri BM et al (2011) MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol 13:423–433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Simons M, Raposo G (2009) Exosomes-vesicular carriers for intercellular communication. Curr Opin Cell Biol 21:575–581

    Article  CAS  PubMed  Google Scholar 

  19. Théry C, Amigorena S, Raposo G et al (2006) Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. doi:10.1002/0471143030

    PubMed  Google Scholar 

  20. Peinado H, Aleckovic M, Lavotshkin S (2012) Melanoma exosomes educate bone marrow progenitor cells toward a prometastatic phenotype through MET. Nat Med 18:883–891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kahlert C, Melo SA, Protopopov A et al (2014) Identification of double-stranded genomic DNA spanning all chromosomes with mutated KRAS and p53 DNA in the serum exosomes of patients with pancreatic cancer. J Biol Chem 289:3869–3875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Waldenström A, Gennebäck N, Hellman U et al (2012) Cardiomyocyte microvesicles contain DNA/RNA and convey biological messages to target cells. PLoS One 7:e34653

    Article  PubMed  PubMed Central  Google Scholar 

  23. Herve JC, Derangeon M (2013) Gap-junction-mediated cell-to-cell communication. Cell Tissue Res 352:21–31

    Article  CAS  PubMed  Google Scholar 

  24. Singer SJ (1992) Intercellular communication and cell-cell adhesion. Science 255:1671–1677

    Article  CAS  PubMed  Google Scholar 

  25. Imagawa W, Pedchenko VK, Helber J et al (2002) Hormone/growth factor interactions mediating epithelial/stromal communication in mammary gland development and carcinogenesis. J Steroid Biochem Mol Biol 80:213–230

    Article  CAS  PubMed  Google Scholar 

  26. Chen WX, Zhong SL, Ji MH et al (2014) MicroRNAs delivered by extracellular vesicles: an emerging resistance mechanism for breast cancer. Tumour Biol 35:2883–2892

    Article  CAS  PubMed  Google Scholar 

  27. Valadi H, Ekstrom K, Bossios A et al (2007) Exosome mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659

    Article  CAS  PubMed  Google Scholar 

  28. Zhang X, Wang X, Zhu H et al (2012) Hsp20 functions as a novel cardiokine in promoting angiogenesis via activation of VEGFR2. PLoS ONE 7:e32765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Malik ZA, Kott KS, Poe AJ et al (2013) Cardiac myocyte exosomes: stability, HSP60, and proteomics. Am J Physiol Heart Circ Physiol 304:H954–965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Raposo G, Stoorvogel W (2013) Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 200:373–383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Thery C, Ostrowski M, Segura E (2009) Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9:581–593

    Article  CAS  PubMed  Google Scholar 

  32. Klionsky DJ, Emr SD (2000) Autophagy as a regulated pathway of cellular degradation. Science 290:1717–1721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Nakatogawa H, Suzuki K, Kamada Y et al (2009) Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol 10:458–467

    Article  CAS  PubMed  Google Scholar 

  34. Yang Z, Klionsky DJ (2010) Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol 22:124–131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kang R, Zeh HJ, Lotze MT et al (2011) The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ 18:571–580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Qu X, Yu J, Bhagat G et al (2003) Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 112:1809–1820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yue Z, Jin SK, Yang CW et al (2003) Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A 100:15077–15082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Xiao J, Zhu X, He B et al (2011) MiR-204 regulates cardiomyocyte autophagy induced by ischemia-reperfusion through LC3-II. J Biomed Sci. doi:10.1186/1423-0127-18-35

    Google Scholar 

  39. Yu Y, Yang L, Zhao M et al (2012) Targeting microRNA-30a-mediated autophagy enhances imatinib activity against human chronic myeloid leukemia cells. Leukemia 26:1752–1760

    Article  CAS  PubMed  Google Scholar 

  40. Maiuri MC, Zalckvar E, Kimchi A et al (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 8:741–752

    Article  CAS  PubMed  Google Scholar 

  41. Nakai A, Yamaguchi O, Takeda T et al (2007) The role of autophagy in myocytes in the basal state and in response to hemodynamic stress. Nat Med 13:619–624

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

    Authors and Affiliations

    1. Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430022, China

      Yan Yang, Yingying Li, Xiao Chen, Xiang Cheng, Yuhua Liao & Xian Yu

    Authors
    1. Yan Yang
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Yingying Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Xiao Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Xiang Cheng
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Yuhua Liao
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Xian Yu
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Yuhua Liao or Xian Yu.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no competing interests.

    Funding information

    This work was supported by the National Natural Science Foundation of China (81300179).

    Additional information

    Yan Yang, Yingying Li and Xiao Chen contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    ESM 1

    (PDF 316 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

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

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00109-016-1387-2

    Keywords

    Search

    Navigation