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Biotechnology Letters

, Volume 39, Issue 7, pp 967–976 | Cite as

Knockdown of microRNA-17-5p ameliorates atherosclerotic lesions in ApoE−/− mice and restores the expression of very low density lipoprotein receptor

  • Lili Tan
  • Liang Meng
  • Xiaojing Shi
  • Bo Yu
Original Research Paper

Abstract

Objective

To propose and verify a hypothesis that miR-17-5p knockdown may mitigate atherosclerotic lesions using atherosclerotic ApoE−/− mice as serum microRNA-17-5p (miR-17-5p) is elevated in patients with atherosclerosis.

Results

The level of miR-17-5p was higher while the level of very low density lipoprotein receptor (VLDLR), a predicted target of miR-17-5p, was lower in the peripheral blood lymphocytes (PBLs) of atherosclerosis patients as compared with control PBLs. ApoE−/− mice fed with a high-cholesterol diet displayed marked atherosclerotic vascular lesions, which were ameliorated after treatment with antagomiR-17-5p. Moreover, the decreased VLDLR in atherosclerotic mice was partly restored when miR-17-5p was antagonized. Further, luciferase assay confirmed VLDLR as a direct target of miR-17-5p in vascular smooth muscle cells (VSMCs). In addition, the elevated expression of proprotein convertase subtilisin kexin 9 (PCSK9), a secreted protease that binds to and promotes VLDLR degradation, in the atherosclerotic mice was suppressed by antagomiR-17-5p.

Conclusions

A novel interaction between miR-17-5p and VLDLR is revealed and suggests that miR-17-5p may be a potential therapeutic target for AS.

Keywords

Atherosclerosis MicroRNA-17-5p Proprotein convertase subtilisin kexin 9 Very low density lipoprotein receptor 

Notes

Supporting information

Supplementary Table 1—Primer information used for RT-PCR analysis.

Supplementary Figure 1—The expression level of VLDLR after treatment with or without antagomiR-17-5p in the heart of atherosclerotic ApoE−/− mice by Western blot analysis.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

10529_2017_2337_MOESM1_ESM.docx (17 kb)
Supplementary material 1 (DOCX 16 kb)
10529_2017_2337_MOESM2_ESM.tif (138 kb)
Supplementary material 2 (TIFF 137 kb)

References

  1. Alvarez ML, Khosroheidari M, Eddy E, Done SC (2015) MicroRNA-27a decreases the level and efficiency of the LDL receptor and contributes to the dysregulation of cholesterol homeostasis. Atherosclerosis 242:595–604CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bentwich I et al (2005) Identification of hundreds of conserved and nonconserved human microRNAs. Nat Genet 37:766–770CrossRefPubMedGoogle Scholar
  3. Casscells W (1992) Migration of smooth muscle and endothelial cells. Crit Events Restenosis Circ 86:723–729Google Scholar
  4. Chen YC et al (2013) A novel mouse model of atherosclerotic plaque instability for drug testing and mechanistic/therapeutic discoveries using gene and microRNA expression profiling. Circ Res 113:252–265CrossRefPubMedGoogle Scholar
  5. Chen J, Xu L, Hu Q, Yang S, Zhang B, Jiang H (2015) MiR-17-5p as circulating biomarkers for the severity of coronary atherosclerosis in coronary artery disease. Int J Cardiol 197:123–124CrossRefPubMedGoogle Scholar
  6. Cheng Y et al (2009) MicroRNA-145, a novel smooth muscle cell phenotypic marker and modulator, controls vascular neointimal lesion formation. Circ Res 105:158–166CrossRefPubMedPubMedCentralGoogle Scholar
  7. Doebele C et al (2010) Members of the microRNA-17-92 cluster exhibit a cell-intrinsic antiangiogenic function in endothelial cells. Blood 115:4944–4950CrossRefPubMedGoogle Scholar
  8. Eck MV et al (2005) Role of the macrophage very-low-density lipoprotein receptor in atherosclerotic lesion development. Atherosclerosis 183:230–237CrossRefPubMedGoogle Scholar
  9. Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114CrossRefPubMedGoogle Scholar
  10. Lusis AJ (2000) Atheroscler Nat 407:233–241Google Scholar
  11. Perez-Sanchez C et al (2016) Atherothrombosis-associated microRNAs in Antiphospholipid syndrome and Systemic Lupus Erythematosus patients. Sci Rep 6:31375CrossRefPubMedPubMedCentralGoogle Scholar
  12. Poirier S et al (2008) The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2. J Biol Chem 283:2363–2372CrossRefPubMedGoogle Scholar
  13. Tacken PJ, Delsing DJ, Gijbels MJ, Quax PH, Havekes LM, Hofker MH, Van Dijk KW (2002) VLDL receptor deficiency enhances intimal thickening after vascular injury but does not affect atherosclerotic lesion area. Atherosclerosis 162:103–110CrossRefPubMedGoogle Scholar
  14. Tiebel O et al (1999) Mouse very low-density lipoprotein receptor (VLDLR): gene structure, tissue-specific expression and dietary and developmental regulation. Atherosclerosis 145:239–251CrossRefPubMedGoogle Scholar
  15. Zhang Y, Ma KL, Ruan XZ, Liu BC (2016) Dysregulation of the low-density lipoprotein receptor pathway is involved in lipid disorder-mediated organ injury. Int J Biol Sci 12:569–579CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2017

Authors and Affiliations

  1. 1.Department of CardiologyThe First Affiliated Hospital of China Medical UniversityShenyangPeople’s Republic of China
  2. 2.Department of CardiologyCentral Hospital Affiliated to Shenyang Medical CollegeShenyangPeople’s Republic of China
  3. 3.Department of CardiologyThe First Affiliated Hospital of Jinzhou Medical UniversityJinzhouPeople’s Republic of China

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