Skip to main content

Advertisement

Log in

MicroRNA-199a-3p Exhibits Beneficial Effects in Asymptomatic Atherosclerosis by Inhibiting Vascular Smooth Muscle Cell Proliferation and Migration

  • Original Paper
  • Published:
Molecular Biotechnology Aims and scope Submit manuscript

Abstract

Atherosclerosis (AS) is a serious healthy burden worldwide, it occurs accompany with the disfunction of vascular smooth muscle cells (VSMCs). MicroRNAs play pivotal role in the pathogenesis of various diseases. This study aimed to investigate the expression and clinical value of miR-199a-3p in patients with asymptomatic AS, and further explore its regulatory role on VSMCs biological function. Quantitative real-time PCR was used to estimate the expression of miR-199a-3p. Correlation of miR-199a-3p with carotid intima-media thickness (CIMT) and C-reactive protein (CRP) was evaluated by Pearson correlation coefficient. A receiver operating characteristic (ROC) curve was plotted to evaluate the diagnostic value of miR-199a-3p. Effects of miR-199a-3p on cell proliferation and migration in VSMCs were analyzed using cell-counting method and Transwell assay. Luciferase reporter assay was performed for the target gene analysis. Serum expression of miR-199a-3p was decreased in asymptomatic AS patients compared with the healthy controls. The negative correlations of miR-199a-3p with CIMT and CRP were obtained. The decreased miR-199a-3p was proved to have diagnostic accuracy with an area under the ROC curve (AUC) of 0.912, and was an independent predictor for the occurrence of asymptomatic AS. In VSMCs, overexpression of miR-199a-3p led to inhibited cell proliferation and migration, while the knockdown of miR-199a-3p resulted in the opposite results. SP1 was proved to be the target gene of miR-199a-3p. Taken together, downregulated expression of miR-199a-3p is a candidate diagnostic biomarker in the patients with asymptomatic AS. Overexpression of miR-199a-3p exists suppressive effects on VSMC proliferation and migration, indicating that miR-199a-3p may be a potential therapeutic target for AS treatment.

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

Access this article

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

Similar content being viewed by others

Data Availability

All data generated or analysed during this study are included in this published article.

References

  1. Zhu, H., Li, Z., Lv, J., & Zhao, R. (2018). Effects of cerebral small vessel disease on the outcome of patients with ischemic stroke caused by large artery atherosclerosis. Neurological Research, 40(5), 381–390.

    Article  Google Scholar 

  2. Ndrepepa, G., Colleran, R., & Kastrati, A. (2018). Gamma-glutamyl transferase and the risk of atherosclerosis and coronary heart disease. Clinica Chimica Acta International Journal of Clinical Chemistry, 476, 130–138.

    Article  CAS  Google Scholar 

  3. Libby, P., Bornfeldt, K. E., & Tall, A. R. (2016). Atherosclerosis: Successes, surprises, and future challenges. Circulation Research, 118(4), 531–534.

    Article  CAS  Google Scholar 

  4. Nezu, T., Hosomi, N., Aoki, S., & Matsumoto, M. (2016). Carotid intima-media thickness for atherosclerosis. Journal of Atherosclerosis and Thrombosis, 23(1), 18–31.

    Article  CAS  Google Scholar 

  5. Ridker, P. M. (2016). From C-reactive protein to interleukin-6 to interleukin-1: Moving upstream to identify novel targets for atheroprotection. Circulation Research, 118(1), 145–156.

    Article  CAS  Google Scholar 

  6. Bennett, M. R., Sinha, S., & Owens, G. K. (2016). Vascular smooth muscle cells in atherosclerosis. Circulation Research, 118(4), 692–702.

    Article  CAS  Google Scholar 

  7. Zheng, J., Chen, K., Wang, H., Chen, Z., Xi, Y., Yin, H., et al. (2018). SIRT7 regulates the vascular smooth muscle cells proliferation and migration via Wnt/beta-catenin signaling pathway. BioMed Research International, 2018, 4769596.

    PubMed  PubMed Central  Google Scholar 

  8. Yang, L., Gao, L., Nickel, T., Yang, J., Zhou, J., Gilbertsen, A., et al. (2017). Lactate promotes synthetic phenotype in vascular smooth muscle cells. Circulation Research, 121(11), 1251–1262.

    Article  CAS  Google Scholar 

  9. Liu, Y., Hu, Y., Ni, D., Liu, J., Xia, H., Xu, L., et al. (2019). miR-194 regulates the proliferation and migration via targeting Hnf1beta in mouse metanephric mesenchyme cells. In Vitro Cellular & Developmental Biology Animal. https://doi.org/10.1007/s11626-019-00366-z.

    Article  Google Scholar 

  10. Zhang, Y., Wang, J., An, W., Chen, C., Wang, W., Zhu, C., et al. (2019). MiR-32 inhibits proliferation and metastasis by targeting EZH2 in glioma. Technology in Cancer Research & Treatment, 18, 1533033819854132.

    CAS  Google Scholar 

  11. Leinders, M., Uceyler, N., Thomann, A., & Sommer, C. (2017). Aberrant microRNA expression in patients with painful peripheral neuropathies. Journal of the Neurological Sciences, 380, 242–249.

    Article  CAS  Google Scholar 

  12. Feinberg, M. W., & Moore, K. J. (2016). MicroRNA regulation of atherosclerosis. Circulation Research, 118(4), 703–720.

    Article  CAS  Google Scholar 

  13. Negoita, S. I., Sandesc, D., Rogobete, A. F., Dutu, M., Bedreag, O. H., Papurica, M., et al. (2017). miRNAs expressions and interaction with biological systems in patients with Alzheimer’s disease. Using miRNAs as a diagnosis and prognosis biomarker. Clinical Laboratory, 63(9), 1315–1321.

    CAS  PubMed  Google Scholar 

  14. Cheng, G. (2015). Circulating miRNAs: Roles in cancer diagnosis, prognosis and therapy. Advanced Drug Delivery Reviews, 81, 75–93.

    Article  CAS  Google Scholar 

  15. Li, X., & Zhong, H. (2016). The diagnosis, prognosis, and therapeutic application of MicroRNAs in haematological malignancies. Hematology, 21(5), 263–271.

    Article  CAS  Google Scholar 

  16. Huang, Y. Q., Li, J., Chen, J. Y., Zhou, Y. L., Cai, A. P., Huang, C., et al. (2017). The association of circulating MiR-29b and interleukin-6 with subclinical atherosclerosis. Cellular Physiology and Biochemistry: International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology., 44(4), 1537–1544.

    Article  CAS  Google Scholar 

  17. Bras, J. P., Silva, A. M., Calin, G. A., Barbosa, M. A., Santos, S. G., & Almeida, M. I. (2017). miR-195 inhibits macrophages pro-inflammatory profile and impacts the crosstalk with smooth muscle cells. PLoS ONE, 12(11), e0188530.

    Article  Google Scholar 

  18. Vegter, E. L., Ovchinnikova, E. S., van Veldhuisen, D. J., Jaarsma, T., Berezikov, E., van der Meer, P., et al. (2017). Low circulating microRNA levels in heart failure patients are associated with atherosclerotic disease and cardiovascular-related rehospitalizations. Clinical Research in Cardiology: Official Journal of the German Cardiac Society, 106(8), 598–609.

    Article  CAS  Google Scholar 

  19. Huang, Y. Q., Jie, L. I., Chen, J. Y., Tang, S. T., Huang, C., & Feng, Y. Q. (2017). The relationship between soluble CD40 ligand level and atherosclerosis in white-coat hypertension. Journal of Human Hypertension, 32(1), 40–45.

    Article  Google Scholar 

  20. Sayed, A. S., Xia, K., Salma, U., Yang, T., & Peng, J. (2014). Diagnosis, prognosis and therapeutic role of circulating miRNAs in cardiovascular diseases. Heart, Lung & Circulation, 23(6), 503–510.

    Article  Google Scholar 

  21. Zhou, X., Lu, Z., Wang, T., Huang, Z., Zhu, W., & Miao, Y. (2018). Plasma miRNAs in diagnosis and prognosis of pancreatic cancer: A miRNA expression analysis. Gene, 673, 181–193.

    Article  CAS  Google Scholar 

  22. Qiu, Z., Li, H., Wang, J., & Sun, C. (2017). miR-146a and miR-146b in the diagnosis and prognosis of papillary thyroid carcinoma. Oncology Reports, 38(5), 2735–2740.

    Article  CAS  Google Scholar 

  23. Xiao, J., Gao, R., Bei, Y., Zhou, Q., Zhou, Y., Zhang, H., et al. (2017). Circulating miR-30d predicts survival in patients with acute heart failure. Cellular Physiology and Biochemistry: International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology, 41(3), 865–874.

    Article  CAS  Google Scholar 

  24. Lin, X., Zhang, S., & Huo, Z. (2019). Serum circulating miR-150 is a predictor of post-acute myocardial infarction heart failure. International Heart Journal, 60(2), 280–286.

    Article  CAS  Google Scholar 

  25. Benz, F., Roderburg, C., Vargas Cardenas, D., Vucur, M., Gautheron, J., Koch, A., et al. (2013). U6 is unsuitable for normalization of serum miRNA levels in patients with sepsis or liver fibrosis. Experimental & Molecular Medicine, 45, e42.

    Article  Google Scholar 

  26. Xiang, M., Zeng, Y., Yang, R., Xu, H., Chen, Z., Zhong, J., et al. (2014). U6 is not a suitable endogenous control for the quantification of circulating microRNAs. Biochemical and Biophysical Research Communications, 454(1), 210–214.

    Article  CAS  Google Scholar 

  27. Appaiah, H. N., Goswami, C. P., Mina, L. A., Badve, S., Sledge, G. W., Jr., Liu, Y., et al. (2011). Persistent upregulation of U6:SNORD44 small RNA ratio in the serum of breast cancer patients. Breast Cancer Research, 13(5), R86.

    Article  CAS  Google Scholar 

  28. Ecke, T. H., Stier, K., Weickmann, S., Zhao, Z., Buckendahl, L., Stephan, C., et al. (2017). miR-199a-3p and miR-214-3p improve the overall survival prediction of muscle-invasive bladder cancer patients after radical cystectomy. Cancer Medicine, 6(10), 2252–2262.

    Article  CAS  Google Scholar 

  29. Chai, C., Song, L. J., Yang, B., Han, S. Y., Li, X. Q., & Li, M. (2016). Circulating miR-199a-3p in plasma and its potential diagnostic and prognostic value in glioma. European Review for Medical and Pharmacological Sciences, 20(23), 4885–4890.

    CAS  PubMed  Google Scholar 

  30. Yin, J., Hou, P., Wu, Z., Wang, T., & Nie, Y. (2015). Circulating miR-375 and miR-199a-3p as potential biomarkers for the diagnosis of hepatocellular carcinoma. Tumour Biology: The Journal of the International Society for Oncodevelopmental Biology and Medicine, 36(6), 4501–4507.

    Article  CAS  Google Scholar 

  31. Navickas, R., Gal, D., Laucevicius, A., Taparauskaite, A., Zdanyte, M., & Holvoet, P. (2016). Identifying circulating microRNAs as biomarkers of cardiovascular disease: A systematic review. Cardiovascular Research, 111(4), 322–337.

    Article  CAS  Google Scholar 

  32. Kurkowska-Jastrzebska, I., Karlinski, M. A., Blazejewska-Hyzorek, B., Sarzynska-Dlugosz, I., Filipiak, K. J., & Czlonkowska, A. (2016). Carotid intima media thickness and blood biomarkers of atherosclerosis in patients after stroke or myocardial infarction. Croatian Medical Journal, 57(6), 548–557.

    Article  CAS  Google Scholar 

  33. Baumer, Y., McCurdy, S., Alcala, M., Mehta, N., Lee, B. H., Ginsberg, M. H., et al. (2017). CD98 regulates vascular smooth muscle cell proliferation in atherosclerosis. Atherosclerosis, 256, 105–114.

    Article  CAS  Google Scholar 

  34. Li, M., Liu, Q., Lei, J., Wang, X., Chen, X., & Ding, Y. (2017). MiR-362-3p inhibits the proliferation and migration of vascular smooth muscle cells in atherosclerosis by targeting ADAMTS1. Biochemical and Biophysical Research Communications, 493(1), 270–276.

    Article  CAS  Google Scholar 

  35. Zhang, R., Sui, L., Hong, X., Yang, M., & Li, W. (2017). MiR-448 promotes vascular smooth muscle cell proliferation and migration in through directly targeting MEF2C. Environmental Science and Pollution Research International, 24(28), 22294–22300.

    Article  Google Scholar 

  36. Cui, C., Wang, X., Shang, X. M., Li, L., Ma, Y., Zhao, G. Y., et al. (2019). lncRNA 430945 promotes the proliferation and migration of vascular smooth muscle cells via the ROR2/RhoA signaling pathway in atherosclerosis. Molecular Medicine Reports, 19(6), 4663–4672.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Azahri, N. S., Di Bartolo, B. A., Khachigian, L. M., & Kavurma, M. M. (2012). Sp1, acetylated histone-3 and p300 regulate TRAIL transcription: Mechanisms of PDGF-BB-mediated VSMC proliferation and migration. Journal of Cellular Biochemistry, 113(8), 2597–2606.

    Article  CAS  Google Scholar 

  38. Shi, J. H., Zheng, B., Chen, S., Ma, G. Y., & Wen, J. K. (2012). Retinoic acid receptor alpha mediates all-trans-retinoic acid-induced Klf4 gene expression by regulating Klf4 promoter activity in vascular smooth muscle cells. Journal of Biological Chemistry, 287(14), 10799–10811.

    Article  CAS  Google Scholar 

  39. Tang, Y., Yu, S., Liu, Y., Zhang, J., Han, L., & Xu, Z. (2017). MicroRNA-124 controls human vascular smooth muscle cell phenotypic switch via Sp1. American Journal of Physiology Heart and Circulatory Physiology, 313(3), H641–H649.

    Article  Google Scholar 

Download references

Funding

No funding was received.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lili Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Ethical Approval

The protocols of this study were approved by the Ethics Committee of the Affiliated Hospital of Weifang Medical University, and written informed consent was obtained from each participant.

Consent to Participate

Informed consent was obtained from all individual participants included in the study.

Consent to Publish

The participant has consented to the submission of the case report to the journal.

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

Sun, X., Zhang, Y., Liu, Z. et al. MicroRNA-199a-3p Exhibits Beneficial Effects in Asymptomatic Atherosclerosis by Inhibiting Vascular Smooth Muscle Cell Proliferation and Migration. Mol Biotechnol 63, 595–604 (2021). https://doi.org/10.1007/s12033-021-00323-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12033-021-00323-w

Keywords

Navigation