Skip to main content

Advertisement

SpringerLink
Log in

SMILR Aggravates the Progression of Atherosclerosis by Sponging miR-10b-3p to Regulate KLF5 Expression

  • Original Article
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Over the past few decades, long noncoding RNAs (lncRNAs) have been widely accepted to be involved in various diseases, and smooth muscle enriched long noncoding RNA (SMILR) was reported to participate in the proliferation of vascular smooth muscle cells (VSMCs). Nevertheless, the molecular mechanisms of SMILR in atherosclerosis (AS) have not been fully explored. In this study, VSMCs and human mononuclear cells (U937) treated with oxidized low-density lipoprotein (ox-LDL) were used as cell models of AS. We found that the expression of SMILR was upregulated in the serum of AS patients and ox-LDL-induced AS cell models. SMILR knockdown inhibited cell proliferation while increasing cell apoptosis in the AS cell models. In addition, SMILR acted as a sponge for miR-10b-3p, and miR-10b-3p counteracted SMILR-mediated regulation of AS. Moreover, we confirmed that miR-10b-3p could bind with KLF5, and SMILR regulated KLF5 expression by competitively binding miR-10b-3p. Furthermore, miR-10b-3p modulated cell proliferation and apoptosis in AS by targeting KLF5. Finally, miR-10b-3p regulated AS progression in vivo by targeting KLF5. Overall, our study demonstrated that SMILR participated in the progression of AS by targeting the miR-10b-3p/KLF5 axis, which may provide some clues for future studies of AS.

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. Ballantyne, M.D., K. Pinel, R. Dakin, A.T. Vesey, L. Diver, R. Mackenzie, R. Garcia, P. Welsh, N. Sattar, G. Hamilton, N. Joshi, M.R. Dweck, J.M. Miano, M. McBride, D.E. Newby, R. McDonald, and A.H. Baker. 2016. Smooth muscle enriched long noncoding RNA (SMILR) regulates cell proliferation. Circulation 133 (21): 2050–2065. https://doi.org/10.1161/circulationaha.115.021019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Cui, Y., L. Yi, J.Z. Zhao, and Y.G. Jiang. 2017. Long noncoding RNA HOXA11-AS functions as miRNA sponge to promote the glioma tumorigenesis through targeting miR-140-5p. DNA and Cell Biology 36 (10): 822–828. https://doi.org/10.1089/dna.2017.3805.

    Article  CAS  PubMed  Google Scholar 

  3. Dey, B.K., A.C. Mueller, and A. Dutta. 2014. Long non-coding RNAs as emerging regulators of differentiation, development, and disease. Transcription 5 (4): e944014. https://doi.org/10.4161/21541272.2014.944014.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Fan, M., J. Bai, T. Ding, X. Yang, Q. Si, and D. Nie. 2019. Adipose-derived stem cell transplantation inhibits vascular inflammatory responses and endothelial dysfunction in rats with atherosclerosis. Yonsei Medical Journal 60 (11): 1036–1044. https://doi.org/10.3349/ymj.2019.60.11.1036.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Garg, P.K., W.T. O’Neal, Y. Mok, G. Heiss, J. Coresh, and K. Matsushita. 2018. Life’s simple 7 and peripheral artery disease risk: the atherosclerosis risk in communities study. American Journal of Preventive Medicine 55 (5): 642–649. https://doi.org/10.1016/j.amepre.2018.06.021.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Gouin, K., K. Peck, T. Antes, J.L. Johnson, C. Li, S.D. Vaturi, R. Middleton, G. de Couto, A.S. Walravens, L. Rodriguez-Borlado, R.R. Smith, L. Marbán, E. Marbán, and A.G. Ibrahim. 2017. A comprehensive method for identification of suitable reference genes in extracellular vesicles. J Extracell Vesicles 6 (1): 1347019. https://doi.org/10.1080/20013078.2017.1347019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. He, C., J.W. Ding, S. Li, H. Wu, Y.R. Jiang, W. Yang, L. Teng, J. Yang, and J. Yang. 2015. The role of long Intergenic noncoding RNA p21 in vascular endothelial cells. DNA and Cell Biology 34 (11): 677–683. https://doi.org/10.1089/dna.2015.2966.

    Article  CAS  PubMed  Google Scholar 

  8. Huang, C., Y.W. Hu, J.J. Zhao, X. Ma, Y. Zhang, F.X. Guo, C.M. Kang, J.B. Lu, J.C. Xiu, Y.H. Sha, J.J. Gao, Y.C. Wang, P. Li, B.M. Xu, L. Zheng, and Q. Wang. 2016. Long noncoding RNA HOXC-AS1 suppresses ox-LDL-induced cholesterol accumulation through promoting HOXC6 expression in THP-1 macrophages. DNA and Cell Biology 35 (11): 722–729. https://doi.org/10.1089/dna.2016.3422.

    Article  CAS  PubMed  Google Scholar 

  9. Huang, X., C. Liu, C. Hao, Q. Tang, R. Liu, S. Lin, L. Zhang, and W. Yan. 2016. Identification of altered microRNAs and mRNAs in the cumulus cells of PCOS patients: miRNA-509-3p promotes oestradiol secretion by targeting MAP 3K8. Reproduction 151 (6): 643–655. https://doi.org/10.1530/rep-16-0071.

    Article  CAS  PubMed  Google Scholar 

  10. Hueso, M., L. De Ramon, E. Navarro, E. Ripoll, J.M. Cruzado, J.M. Grinyo, and J. Torras. 2016. Silencing of CD40 in vivo reduces progression of experimental atherogenesis through an NF-kappaB/miR-125b axis and reveals new potential mediators in the pathogenesis of atherosclerosis. Atherosclerosis 255: 80–89. https://doi.org/10.1016/j.atherosclerosis.2016.11.002.

    Article  CAS  PubMed  Google Scholar 

  11. Huo, W., Y. Hou, Y. Li, and H. Li. 2019. Downregulated lncRNA-MIAT confers protection against erectile dysfunction by downregulating lipoprotein lipase via activation of miR-328a-5p in diabetic rats. Biochimica et Biophysica Acta - Molecular Basis of Disease 1865 (6): 1226–1240. https://doi.org/10.1016/j.bbadis.2019.01.018.

    Article  CAS  PubMed  Google Scholar 

  12. Li, M., Q. Liu, J. Lei, X. Wang, X. Chen, and Y. Ding. 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. https://doi.org/10.1016/j.bbrc.2017.09.031.

    Article  CAS  PubMed  Google Scholar 

  13. Li, Y., D. Guo, Y. Zhao, M. Ren, G. Lu, Y. Wang, J. Zhang, C. Mi, S. He, and X. Lu. 2018. Long non-coding RNA SNHG5 promotes human hepatocellular carcinoma progression by regulating miR-26a-5p/GSK3beta signal pathway. Cell Death & Disease 9 (9): 888. https://doi.org/10.1038/s41419-018-0882-5.

    Article  CAS  Google Scholar 

  14. Li, Z., Q. Lu, D. Zhu, Y. Han, X. Zhou, and T. Ren. 2018. Lnc-SNHG1 may promote the progression of non-small cell lung cancer by acting as a sponge of miR-497. Biochemical and Biophysical Research Communications 506 (3): 632–640. https://doi.org/10.1016/j.bbrc.2018.10.086.

    Article  CAS  PubMed  Google Scholar 

  15. Li, S., X. Pan, S. Yang, A. Ma, S. Yin, Y. Dong, H. Pei, X. Bi, and W. Li. 2019. LncRNA MALAT1 promotes oxidized low-density lipoprotein-induced autophagy in HUVECs by inhibiting the PI3K/AKT pathway. Journal of Cellular Biochemistry 120 (3): 4092–4101. https://doi.org/10.1002/jcb.27694.

    Article  CAS  PubMed  Google Scholar 

  16. Mahmoud, A.D., M.D. Ballantyne, V. Miscianinov, K. Pinel, J. Hung, J.P. Scanlon, J. Iyinikkel, J. Kaczynski, A.S. Tavares, A.C. Bradshaw, N.L. Mills, D.E. Newby, A. Caporali, G.W. Gould, S.J. George, I. Ulitsky, J.C. Sluimer, J. Rodor, and A.H. Baker. 2019. The human-specific and smooth muscle cell-enriched LncRNA SMILR promotes proliferation by regulating mitotic CENPF mRNA and drives cell-cycle progression which can be targeted to limit vascular remodeling. Circulation Research 125 (5): 535–551. https://doi.org/10.1161/circresaha.119.314876.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mao, A., M. Chen, Q. Qin, Z. Liang, W. Jiang, W. Yang, and C. Wei. 2019. ZBTB7A promotes migration, invasion and metastasis of human breast cancer cells through NF-kappaB-induced epithelial-mesenchymal transition in vitro and in vivo. Journal of Biochemistry 166 (6): 485–493. https://doi.org/10.1093/jb/mvz062.

    Article  CAS  PubMed  Google Scholar 

  18. Masoumi, F., S. Ghorbani, F. Talebi, W.G. Branton, S. Rajaei, C. Power, and F. Noorbakhsh. 2019. Malat1 long noncoding RNA regulates inflammation and leukocyte differentiation in experimental autoimmune encephalomyelitis. Journal of Neuroimmunology 328: 50–59. https://doi.org/10.1016/j.jneuroim.2018.11.013.

    Article  CAS  PubMed  Google Scholar 

  19. Nalli, Y., M.S. Dar, N. Bano, J.U. Rasool, A.R. Sarkar, J. Banday, A.Q. Bhat, B. Rafia, R.A. Vishwakarma, M.J. Dar, and A. Ali. 2019. Analyzing the role of cannabinoids as modulators of Wnt/beta-catenin signaling pathway for their use in the management of neuropathic pain. Bioorganic & Medicinal Chemistry Letters 29 (9): 1043–1046. https://doi.org/10.1016/j.bmcl.2019.03.013.

    Article  CAS  Google Scholar 

  20. Pircher, A., L. Treps, N. Bodrug, and P. Carmeliet. 2016. Endothelial cell metabolism: a novel player in atherosclerosis? Basic principles and therapeutic opportunities. Atherosclerosis 253: 247–257. https://doi.org/10.1016/j.atherosclerosis.2016.08.011.

    Article  CAS  PubMed  Google Scholar 

  21. Salemi, M., R. Cannarella, R.A. Condorelli, L. Cimino, F. Ridolfo, G. Giurato, C. Romano, S. La Vignera, and A.E. Calogero. 2019. Evidence for long noncoding RNA GAS5 up-regulation in patients with Klinefelter syndrome. BMC Medical Genetics 20 (1): 4. https://doi.org/10.1186/s12881-018-0744-0.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Schaftenaar, F., V. Frodermann, J. Kuiper, and E. Lutgens. 2016. Atherosclerosis: the interplay between lipids and immune cells. Current Opinion in Lipidology 27 (3): 209–215. https://doi.org/10.1097/mol.0000000000000302.

    Article  CAS  PubMed  Google Scholar 

  23. Siemeni, T., A.K. Knofel, N. Madrahimov, W. Sommer, M. Avsar, J. Salman, F. Ius, et al. 2016. In vivo development of transplant arteriosclerosis in humanized mice reflects alloantigen recognition and peripheral Treg phenotype of lung transplant recipients. American Journal of Transplantation 16 (11): 3150–3162. https://doi.org/10.1111/ajt.13905.

    Article  CAS  PubMed  Google Scholar 

  24. Sueta, D., S. Hokimoto, K. Sakamoto, T. Akasaka, N. Tabata, K. Kaikita, O. Honda, M. Naruse, and H. Ogawa. 2017. Validation of the high mortality rate of malnutrition-inflammation-atherosclerosis syndrome: community-based observational study. International Journal of Cardiology 230: 97–102. https://doi.org/10.1016/j.ijcard.2016.12.072.

    Article  PubMed  Google Scholar 

  25. Tao, F., X. Tian, M. Lu, and Z. Zhang. 2018. A novel lncRNA, Lnc-OC1, promotes ovarian cancer cell proliferation and migration by sponging miR-34a and miR-34c. Journal of Genetics and Genomics 45 (3): 137–145. https://doi.org/10.1016/j.jgg.2018.03.001.

    Article  PubMed  Google Scholar 

  26. Wang, J., Y. Chu, M. Xu, X. Zhang, Y. Zhou, and M. Xu. 2019. miR-21 promotes cell migration and invasion of hepatocellular carcinoma by targeting KLF5. Oncology Letters 17 (2): 2221–2227. https://doi.org/10.3892/ol.2018.9843.

    Article  CAS  PubMed  Google Scholar 

  27. Wang, W., Y. Zhang, L. Wang, J. Li, Y. Li, X. Yang, and Y. Wu. 2019. mircroRNA-152 prevents the malignant progression of atherosclerosis via down-regulation of KLF5. Biomedicine & Pharmacotherapy 109: 2409–2414. https://doi.org/10.1016/j.biopha.2018.08.014.

    Article  CAS  Google Scholar 

  28. Wu, Y., J. Qin, F. Li, C. Yang, Z. Li, Z. Zhou, H. Zhang, et al. 2019. USP3 promotes breast cancer cell proliferation by deubiquitinating KLF5. The Journal of Biological Chemistry. https://doi.org/10.1074/jbc.RA119.009102.

  29. Zhang, J.Z., D. Chen, L.Q. Lv, Z. Xu, Y.M. Li, J.Y. Wang, K.W. Han, M.K. Yu, C.G. Huang, and L.J. Hou. 2018. miR-448-3p controls intracranial aneurysm by regulating KLF5 expression. Biochemical and Biophysical Research Communications 505 (4): 1211–1215. https://doi.org/10.1016/j.bbrc.2018.10.032.

    Article  CAS  PubMed  Google Scholar 

  30. Zhong, X., X. Ma, L. Zhang, Y. Li, Y. Li, and R. He. 2018. MIAT promotes proliferation and hinders apoptosis by modulating miR-181b/STAT3 axis in ox-LDL-induced atherosclerosis cell models. Biomedicine & Pharmacotherapy 97: 1078–1085. https://doi.org/10.1016/j.biopha.2017.11.052.

    Article  CAS  Google Scholar 

  31. Zhou, T., S. Chen, and X. Mao. 2019. miR-145-5p affects the differentiation of gastric cancer by targeting KLF5 directly. Journal of Cellular Physiology 234 (5): 7634–7644. https://doi.org/10.1002/jcp.27525.

    Article  CAS  PubMed  Google Scholar 

  32. Zhu, H., T. Zhao, and J. Liu. 2018. Role of paraoxonase 1 activity and oxidative/antioxidative stress markers in patients with acute cerebral infarction. Clinical Laboratory 64 (6): 1049–1053. https://doi.org/10.7754/Clin.Lab.2018.180201.

    Article  CAS  PubMed  Google Scholar 

  33. Zhu, X., W. Li, and H. Li. 2018. miR-214 ameliorates acute kidney injury via targeting DKK3 and activating of Wnt/beta-catenin signaling pathway. Biol Res 51 (1): 31. https://doi.org/10.1186/s40659-018-0179-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We are grateful to all the participants in this work.

Author information

Authors and Affiliations

  1. Department of Vascular Surgery, Minhang Hospital, Fudan University, No. 39 Xinling Road, Minhang District, 201199, Shanghai, China

    Huaqing Li, Zhiyu Pan, Qian Chen, Zhen Yang & Dongbing Zhang

Authors
  1. Huaqing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhiyu Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qian Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhen Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dongbing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhiyu Pan.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflicts 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

Li, H., Pan, Z., Chen, Q. et al. SMILR Aggravates the Progression of Atherosclerosis by Sponging miR-10b-3p to Regulate KLF5 Expression. Inflammation 43, 1620–1633 (2020). https://doi.org/10.1007/s10753-020-01237-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-020-01237-6

KEY WORDS

Search

Navigation