miRNA Profiling of Exosomes from Spontaneous Hypertensive Rats Using Next-Generation Sequencing

  • Xiaoyan Liu
  • Wen Yuan
  • Lei Yang
  • Jing Li
  • Jun CaiEmail author


The role and miRNA expression profile of exosomes in hypertension remain largely unknown. Therefore, next-generation sequencing was used to define the miRNA expression profile of plasma exosomes in spontaneously hypertensive rats (SHRs), the most widely used animal model of human essential hypertension, and their controls, normotensive Wistar-Kyoto rats (WKYs). Results revealed that percentages of miRNA in the total small RNA isolated from SHRs and WKYs were not significantly different. Twenty-seven miRNAs were significantly differentially expressed (DE) between SHR and WKY exosomes, including 23 up-regulated and four down-regulated in SHR exosomes as compared to WKY exosomes. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis of top 10 DE miRNAs identified hypertension-specific target genes/signaling pathways. In conclusion, our findings indicated the selective packing of miRNA cargo into exosomes under hypertensive status, which could facilitate the development of potential targets for the diagnosis, prevention, and treatment of hypertension.


Exosomes Hypertension miRNA 



Next-generation sequencing


Spontaneously hypertensive rats


Wistar-Kyoto rats


Gene Ontology


Kyoto Encyclopedia of Genes and Genomes


Ethylenediaminetetraacetic acid


Differentially expressed


Candidate target genes


Systolic blood pressure


Diastolic blood pressure


Heart rate


Sources of Funding

This work was supported by National Natural Science Foundation of China (81470541, 81500038, 81630014), National Basic Research Program of China (973 Program, 2014CB542302), CAMS Innovation Fund for Medical Sciences(CIFMS, 2016-12M-1-006), Beijing Municipal Science and Technology Commission (Z151100002115050, Z151100004015176), Beijing Municipal Commission of Education (KZ201610025028), and Beijing Municipal Natural Science Foundation (7172078).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human Subjects/Informed Consent Statement

No human studies were conducted.

Ethical Approval of Animal Studies

All institutional and national guidelines for the care and use of laboratory animals were followed and approved by the appropriate institutional committees.


  1. 1.
    Li, L., Li, C., Wang, S., Wang, Z., Jiang, J., Wang, W., et al. (2016). Exosomes derived from hypoxic oral squamous cell carcinoma cells deliver miR-21 to normoxic cells to elicit a prometastatic phenotype. Cancer Research, 76(7), 1770–1780.Google Scholar
  2. 2.
    Pierdomenico, S. D., Di Nicola, M., Esposito, A. L., Di Mascio, R., Ballone, E., Lapenna, D., et al. (2009). Prognostic value of different indices of blood pressure variability in hypertensive patients. American Journal of Hypertension, 22(8), 842–847.Google Scholar
  3. 3.
    Leung, A., Trac, C., Jin, W., Lanting, L., Akbany, A., Saetrom, P., et al. (2013). Novel long noncoding RNAs are regulated by angiotensin II in vascular smooth muscle cells. Circulation Research, 113(3), 266–278.Google Scholar
  4. 4.
    Thery, C., Zitvogel, L., & Amigorena, S. (2002). Exosomes: Composition, biogenesis and function. Nature Reviews. Immunology, 2(8), 569–579.Google Scholar
  5. 5.
    Thompson, A. G., Gray, E., Heman-Ackah, S. M., Mager, I., Talbot, K., Andaloussi, S. E., et al. (2016). Extracellular vesicles in neurodegenerative disease—pathogenesis to biomarkers. Nature Reviews. Neurology, 12(6), 346–357.Google Scholar
  6. 6.
    Richards, K. E., Zeleniak, A. E., Fishel, M. L., Wu, J., Littlepage, L. E., & Hill, R. (2017). Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. Oncogene, 36(13), 1770–1778.Google Scholar
  7. 7.
    Srikanthan, S., Li, W., Silverstein, R. L., & McIntyre, T. M. (2014). Exosome poly-ubiquitin inhibits platelet activation, downregulates CD36 and inhibits pro-atherothombotic cellular functions. Journal of Thrombosis and Haemostasis, 12(11), 1906–1917.Google Scholar
  8. 8.
    Tkach, M., & Thery, C. (2016). Communication by extracellular vesicles: where we are and where we need to go. Cell, 164(6), 1226–1232.Google Scholar
  9. 9.
    Boulanger, C. M., Loyer, X., Rautou, P. E., & Amabile, N. (2017). Extracellular vesicles in coronary artery disease. Nature Reviews. Cardiology, 14(5), 259–272.Google Scholar
  10. 10.
    Cocucci, E., Racchetti, G., & Meldolesi, J. (2009). Shedding microvesicles: artefacts no more. Trends in Cell Biology, 19(2), 43–51.Google Scholar
  11. 11.
    Au, Y. C., Co, N. N., Tsuruga, T., Yeung, T. L., Kwan, S. Y., Leung, C. S., et al. (2016). Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1. Nature Communications, 7, 11150.Google Scholar
  12. 12.
    Deng, Z., Rong, Y., Teng, Y., Zhuang, X., Samykutty, A., Mu, J., et al. (2017). Exosomes miR-126a released from MDSC induced by DOX treatment promotes lung metastasis. Oncogene, 36(5), 639–651.Google Scholar
  13. 13.
    Nguyen, M.A., Karunakaran, D., Geoffrion, M., Cheng, H.S., Tandoc, K., & Perisic, M.L., et al. (2017). Extracellular vesicles secreted by atherogenic macrophages transfer MicroRNA to inhibit cell migration. Arterioscler Thromb Vasc Biol.Google Scholar
  14. 14.
    Figueroa, J., Phillips, L.M., Shahar, T., Hossain, A., Gumin, J., & Kim, H., et al. (2017). Exosomes from glioma-associated mesenchymal stem cells increase the tumorigenicity of glioma stem-like cells via transfer of miR-1587. Cancer Res.Google Scholar
  15. 15.
    Yang, V. K., Loughran, K. A., Meola, D. M., Juhr, C. M., Thane, K. E., Davis, A. M., et al. (2017). Circulating exosome microRNA associated with heart failure secondary to myxomatous mitral valve disease in a naturally occurring canine model. J Extracell Vesicles, 6(1), 1350088.Google Scholar
  16. 16.
    Teng, Y., Ren, Y., Hu, X., Mu, J., Samykutty, A., Zhuang, X., et al. (2017). MVP-mediated exosomal sorting of miR-193a promotes colon cancer progression. Nature Communications, 8, 14448.Google Scholar
  17. 17.
    Warde-Farley, D., Donaldson, S. L., Comes, O., Zuberi, K., Badrawi, R., Chao, P., et al. (2010). The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Research, 38(Web Server issue), W214–W220.Google Scholar
  18. 18.
    von Mering, C., Huynen, M., Jaeggi, D., Schmidt, S., Bork, P., & Snel, B. (2003). STRING: a database of predicted functional associations between proteins. Nucleic Acids Research, 31(1), 258–261.Google Scholar
  19. 19.
    Fu, S. J., Chen, J., Ji, F., Ju, W. Q., Zhao, Q., Chen, M. G., et al. (2017). MiR-486-5p negatively regulates oncogenic NEK2 in hepatocellular carcinoma. Oncotarget, 8(32), 52948–52959.Google Scholar
  20. 20.
    Sun, Y., Su, Q., Li, L., Wang, X., Lu, Y., & Liang, J. (2017). MiR-486 regulates cardiomyocyte apoptosis by p53-mediated BCL-2 associated mitochondrial apoptotic pathway. BMC Cardiovascular Disorders, 17(1), 119.Google Scholar
  21. 21.
    Pravenec, M., Kren, V., Landa, V., Mlejnek, P., Musilova, A., Silhavy, J., et al. (2014). Recent progress in the genetics of spontaneously hypertensive rats. Physiological Research, 63(Suppl 1), S1–S8.Google Scholar
  22. 22.
    Burke, J., Kolhe, R., Hunter, M., Isales, C., Hamrick, M., & Fulzele, S. (2016). Stem cell-derived exosomes: a potential alternative therapeutic agent in orthopaedics. Stem Cells International, 2016, 5802529.Google Scholar
  23. 23.
    Iraci, N., Leonardi, T., Gessler, F., Vega, B., & Pluchino, S. (2016). Focus on extracellular vesicles: physiological role and signalling properties of extracellular membrane vesicles. International Journal of Molecular Sciences, 17(2), 171.Google Scholar
  24. 24.
    Wu, C., Arora, P., Agha, O., Hurst, L. A., Allen, K., Nathan, D. I., et al. (2016). Novel MicroRNA regulators of atrial natriuretic peptide production. Molecular and Cellular Biology, 36(14), 1977–1987.Google Scholar
  25. 25.
    Yin, J., Liu, H., Huan, L., Song, S., Han, L., Ren, F., et al. (2017). Role of miR-128 in hypertension-induced myocardial injury. Experimental and Therapeutic Medicine, 14(4), 2751–2756.Google Scholar
  26. 26.
    Osada-Oka, M., Shiota, M., Izumi, Y., Nishiyama, M., Tanaka, M., Yamaguchi, T., et al. (2017). Macrophage-derived exosomes induce inflammatory factors in endothelial cells under hypertensive conditions. Hypertension Research, 40(4), 353–360.Google Scholar
  27. 27.
    Liu, X., Fortin, K., & Mourelatos, Z. (2008). MicroRNAs: biogenesis and molecular functions. Brain Pathology, 18(1), 113–121.Google Scholar
  28. 28.
    Raman, M., & Cobb, M. H. (2006). TGF-beta regulation by Emilin1: new links in the etiology of hypertension. Cell, 124(5), 893–895.Google Scholar
  29. 29.
    Liu, X., Hu, C., Bao, M., Li, J., Liu, X., & Tan, X., et al. (2016). Genome wide association study identifies L3MBTL4 as a novel susceptibility gene for hypertension. Scientific Reports, 6(1), 30811.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Xiaoyan Liu
    • 1
    • 2
  • Wen Yuan
    • 1
  • Lei Yang
    • 1
  • Jing Li
    • 2
  • Jun Cai
    • 3
    Email author
  1. 1.Medical Research Center, Beijing Chaoyang HospitalCapital Medical UniversityBeijingChina
  2. 2.Heart Center & Beijing Key Laboratory of Hypertension Research, Beijing Chaoyang HospitalCapital Medical UniversityBeijingChina
  3. 3.Hypertension Center of Fuwai Hospital, State Key Laboratory of Cardiovascular Disease of China, National Center for Cardiovascular Diseases of ChinaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina

Personalised recommendations