Skip to content
2000
image of Circ-LRP6 Inhibits the Development and Progression of AAA Via miR-29a-3p/HIF-1α Axis

Abstract

Background

At present, the research on the potential molecular mechanism of abdominal aortic aneurysm (AAA) is limited, which hinders the treatment of aneurysm and the development of drugs. CircRNA has been identified as a potential therapeutic target for diagnostic biomarkers in a variety of diseases. The purpose of this study was to explore the molecular mechanism of circLRP6 in AAA and to provide a theoretical basis for further clinical optimization of treatment.

Methods

The animal model and cell model of AAA were constructed, and the circLRP6 expression was verified by in situ hybridization and qRT-PCR. The effect of circLRP6 on cell viability was determined using CCK-8 and BrdU. The effects of circLRP6 on the cell cycle and apoptosis were determined by flow cytometry. In addition, the interaction of circLRP6 with miR-29a-3p and HIF-1α was verified by the luciferase reporter gene and RIP. HIF-1α or caspase 3 expression was detected by immunofluorescence or western blot analysis.

Results

Our previous results showed that the circLRP6 had reduced expression in AAA, and its overexpression significantly inhibited AngII-induced hAoSMC cell viability. In addition, bioinformatics prediction showed that there was a binding site between miR-29a-3p and circLRP6, showing a negative regulatory relationship in hAoSMC. In addition, the results of the luciferase reporter gene and RIP showed that the circLRP6 interacted with HIF-1α, and achieved effective treatment of AAA by inhibiting the miR-29a-3p/HIF-1α.

Conclusion

CircLRP6 effectively inhibited the development of AAA by inhibiting the miR-29a-3p/HIF-1α, providing a theoretical basis for further clinical optimization of treatment.

Loading

Article metrics loading...

/content/journals/cpb/10.2174/0113892010327133250424073216
2025-05-12
2025-09-19
Loading full text...

Full text loading...

References

  1. Tchana-Sato V. Sakalihasan N. Defraigne J.O. Ruptured abdominal aortic aneurysm. Rev. Med. Liege 2018 73 5-6 296 299 29926569
    [Google Scholar]
  2. Clancy K. Wong J. Spicher A. Abdominal aortic aneurysm: A case report and literature review. Perm. J. 2019 23 4 18.218 10.7812/TPP/18.218 31926569
    [Google Scholar]
  3. Schmitz-Rixen T. Keese M. Hakimi M. Peters A. Böckler D. Nelson K. Grundmann R.T. Ruptured abdominal aortic aneurysm—epidemiology, predisposing factors, and biology. Langenbecks Arch. Surg. 2016 401 3 275 288 10.1007/s00423‑016‑1401‑8 27001684
    [Google Scholar]
  4. Nguyen V.L. Leiner T. Hellenthal F.A.M.V.I. Backes W.H. Wishaupt M.C.J. van der Geest R.J. Heeneman S. Kooi M.E. Schurink G.W.H. Abdominal aortic aneurysms with high thrombus signal intensity on magnetic resonance imaging are associated with high growth rate. Eur. J. Vasc. Endovasc. Surg. 2014 48 6 676 684 10.1016/j.ejvs.2014.04.025 24935911
    [Google Scholar]
  5. Wang Y. Liu Z. Ren J. Xiang M.X. Pharmacological therapy of abdominal aortic aneurysm: An update. Curr. Vasc. Pharmacol. 2018 16 2 114 124 10.2174/1570161115666170413145705 28412911
    [Google Scholar]
  6. Anagnostakos J. Lal B.K. Abdominal aortic aneurysms. Prog. Cardiovasc. Dis. 2021 65 34 43 10.1016/j.pcad.2021.03.009 33831398
    [Google Scholar]
  7. Nemeth K. Bayraktar R. Ferracin M. Calin G.A. Non-coding RNAs in disease: From mechanisms to therapeutics. Nat. Rev. Genet. 2024 25 3 211 232 10.1038/s41576‑023‑00662‑1 37968332
    [Google Scholar]
  8. Salzman J. Circular RNA expression: Its potential regulation and function. Trends Genet. 2016 32 5 309 316 10.1016/j.tig.2016.03.002 27050930
    [Google Scholar]
  9. Hsiao K.Y. Sun H.S. Tsai S.J. Circular RNA – New member of noncoding RNA with novel functions. Exp. Biol. Med. (Maywood) 2017 242 11 1136 1141 10.1177/1535370217708978 28485684
    [Google Scholar]
  10. Qu S. Yang X. Li X. Wang J. Gao Y. Shang R. Sun W. Dou K. Li H. Circular R.N.A. Circular RNA: A new star of noncoding RNAs. Cancer Lett. 2015 365 2 141 148 10.1016/j.canlet.2015.06.003 26052092
    [Google Scholar]
  11. Wang J. Sun H. Zhou Y. Huang K. Que J. Peng Y. Wang J. Lin C. Xue Y. Ji K. Circular RNA microarray expression profile in 3,4‐benzopyrene/angiotensin II‐induced abdominal aortic aneurysm in mice. J. Cell. Biochem. 2019 120 6 10484 10494 10.1002/jcb.28333 30614051
    [Google Scholar]
  12. Zhou M. Shi Z. Cai L. Li X. Ding Y. Xie T. Fu W. Circular RNA expression profile and its potential regulative role in human abdominal aortic aneurysm. BMC Cardiovasc. Disord. 2020 20 1 70 10.1186/s12872‑020‑01374‑8 32039711
    [Google Scholar]
  13. Di Gregoli K. Mohamad Anuar N.N. Bianco R. White S.J. Newby A.C. George S.J. Johnson J.L. MicroRNA-181b controls atherosclerosis and aneurysms through regulation of TIMP-3 and elastin. Circ. Res. 2017 120 1 49 65 10.1161/CIRCRESAHA.116.309321 27756793
    [Google Scholar]
  14. Zheng C. Niu H. Li M. Zhang H. Yang Z. Tian L. Wu Z. Li D. Chen X. Cyclic RNA has-circ-000595 regulates apoptosis of aortic smooth muscle cells. Mol. Med. Rep. 2015 12 5 6656 6662 10.3892/mmr.2015.4264 26324352
    [Google Scholar]
  15. Qian G. Adeyanju O. Olajuyin A. Guo X. Abdominal aortic aneurysm formation with a focus on vascular smooth muscle cells. Life (Basel) 2022 12 2 191 10.3390/life12020191 35207478
    [Google Scholar]
  16. Qian H. Yang Y. Li J. Huang J. Dou K. Yang G. The role of vascular stem cells in atherogenesis and post-angioplasty restenosis. Ageing Res. Rev. 2007 6 2 109 127 10.1016/j.arr.2007.01.001 17324640
    [Google Scholar]
  17. Lu H. Du W. Ren L. Hamblin M.H. Becker R.C. Chen Y.E. Fan Y. Vascular smooth muscle cells in aortic aneurysm: From genetics to mechanisms. J. Am. Heart Assoc. 2021 10 24 e023601 10.1161/JAHA.121.023601 34796717
    [Google Scholar]
  18. Rombouts K.B. van Merrienboer T.A.R. Ket J.C.F. Bogunovic N. van der Velden J. Yeung K.K. The role of vascular smooth muscle cells in the development of aortic aneurysms and dissections. Eur. J. Clin. Invest. 2022 52 4 e13697 10.1111/eci.13697 34698377
    [Google Scholar]
  19. Bai Y. Liu F. Yang Z. CircRNA LRP6 promotes high-glucose induced proliferation and migration of vascular smooth muscle cells through regulating miR-545-3p/HMGA1 signaling axis. Am. J. Transl. Res. 2021 13 8 8909 8920 34540004
    [Google Scholar]
  20. Rouleau S. Glouzon J.P.S. Brumwell A. Bisaillon M. Perreault J.P. 3′ UTR G-quadruplexes regulate miRNA binding. RNA 2017 23 8 1172 1179 10.1261/rna.060962.117 28473452
    [Google Scholar]
  21. Sun Y. Zong C. Liu J. Zeng L. Li Q. Liu Z. Li Y. Zhu J. Li L. Zhang C. Zhang W. C-myc promotes miR-92a-2-5p transcription in rat ovarian granulosa cells after cadmium exposure. Toxicol. Appl. Pharmacol. 2021 421 115536 10.1016/j.taap.2021.115536 33865896
    [Google Scholar]
  22. Kristensen L.S. Andersen M.S. Stagsted L.V.W. Ebbesen K.K. Hansen T.B. Kjems J. The biogenesis, biology and characterization of circular RNAs. Nat. Rev. Genet. 2019 20 11 675 691 10.1038/s41576‑019‑0158‑7 31395983
    [Google Scholar]
  23. Yue J. Zhu T. Yang J. Si Y. Xu X. Fang Y. Fu W. CircCBFB-mediated miR-28-5p facilitates abdominal aortic aneurysm via LYPD3 and GRIA4. Life Sci. 2020 253 117533 10.1016/j.lfs.2020.117533 32151690
    [Google Scholar]
  24. Hall I.F. Climent M. Quintavalle M. Farina F.M. Schorn T. Zani S. Carullo P. Kunderfranco P. Civilini E. Condorelli G. Elia L. Circ_Lrp6, a circular RNA enriched in vascular smooth muscle cells, acts as a sponge regulating miRNA-145 function. Circ. Res. 2019 124 4 498 510 10.1161/CIRCRESAHA.118.314240 30582454
    [Google Scholar]
  25. Boon R.A. Seeger T. Heydt S. Fischer A. Hergenreider E. Horrevoets A.J.G. Vinciguerra M. Rosenthal N. Sciacca S. Pilato M. van Heijningen P. Essers J. Brandes R.P. Zeiher A.M. Dimmeler S. MicroRNA-29 in aortic dilation: Implications for aneurysm formation. Circ. Res. 2011 109 10 1115 1119 10.1161/CIRCRESAHA.111.255737 21903938
    [Google Scholar]
  26. Maegdefessel L. Azuma J. Toh R. Merk D.R. Deng A. Chin J.T. Raaz U. Schoelmerich A.M. Raiesdana A. Leeper N.J. McConnell M.V. Dalman R.L. Spin J.M. Tsao P.S. Inhibition of microRNA-29b reduces murine abdominal aortic aneurysm development. J. Clin. Invest. 2012 122 2 497 506 10.1172/JCI61598 22269326
    [Google Scholar]
  27. Kasivisvanathan V. Shalhoub J. Lim C.S. Shepherd A.C. Thapar A. Davies A.H. Hypoxia-inducible factor-1 in arterial disease: A putative therapeutic target. Curr. Vasc. Pharmacol. 2011 9 3 333 349 10.2174/157016111795495602 20807188
    [Google Scholar]
  28. Bao M.H. Li G.Y. Huang X.S. Tang L. Dong L.P. Li J.M. Long noncoding RNA LINC00657 acting as a miR-590-3p sponge to facilitate low concentration oxidized low-density lipoprotein-induced angiogenesis. Mol. Pharmacol. 2018 93 4 368 375 10.1124/mol.117.110650 29436491
    [Google Scholar]
  29. Tsai S.H. Huang P.H. Hsu Y.J. Peng Y.J. Lee C.H. Wang J.C. Chen J.W. Lin S.J. Inhibition of hypoxia inducible factor-1α attenuates abdominal aortic aneurysm progression through the down-regulation of matrix metalloproteinases. Sci. Rep. 2016 6 1 28612 10.1038/srep28612 27363580
    [Google Scholar]
  30. Lim C.S. Kiriakidis S. Sandison A. Paleolog E.M. Davies A.H. Hypoxia-inducible factor pathway and diseases of the vascular wall. J. Vasc. Surg. 2013 58 1 219 230 10.1016/j.jvs.2013.02.240 23643279
    [Google Scholar]
  31. Yang L. Shen L. Li G. Yuan H. Jin X. Wu X. Silencing of hypoxia inducible factor-1α gene attenuated angiotensin Ⅱ-induced abdominal aortic aneurysm in apolipoprotein E-deficient mice. Atherosclerosis 2016 252 40 49 10.1016/j.atherosclerosis.2016.07.010 27497884
    [Google Scholar]
  32. Wang W. Xu B. Xuan H. Ge Y. Wang Y. Wang L. Huang J. Fu W. Michie S.A. Dalman R.L. Hypoxia-inducible factor 1 in clinical and experimental aortic aneurysm disease. J. Vasc. Surg. 2018 68 1538 1550
    [Google Scholar]
  33. Bruhn P.J. Jessen M.L. Eiberg J. Ghulam Q. HIF-1α in the pathogenesis of abdominal aortic aneurysms in vivo: A narrative review. JVS Vasc. Sci. 2023 5 100189 10.1016/j.jvssci.2023.100189 38379781
    [Google Scholar]
  34. Li D.Y. Busch A. Jin H. Chernogubova E. Pelisek J. Karlsson J. Sennblad B. Liu S. Lao S. Hofmann P. Bäcklund A. Eken S.M. Roy J. Eriksson P. Dacken B. Ramanujam D. Dueck A. Engelhardt S. Boon R.A. Eckstein H.H. Spin J.M. Tsao P.S. Maegdefessel L. H19 induces abdominal aortic aneurysm development and progression. Circulation 2018 138 15 1551 1568 10.1161/CIRCULATIONAHA.117.032184 29669788
    [Google Scholar]
  35. He X. Wang S. Li M. Zhong L. Zheng H. Sun Y. Lai Y. Chen X. Wei G. Si X. Han Y. Huang S. Li X. Liao W. Liao Y. Bin J. Long noncoding RNA GAS5 induces abdominal aortic aneurysm formation by promoting smooth muscle apoptosis. Theranostics 2019 9 19 5558 5576 10.7150/thno.34463 31534503
    [Google Scholar]
  36. Liu S. Zhou H. Han D. Song H. Li Y. He S. Du Y. Wang K. Huang X. Li X. Huang Z. LncRNA CARMN inhibits abdominal aortic aneurysm formation and vascular smooth muscle cell phenotypic transformation by interacting with SRF. Cell. Mol. Life Sci. 2024 81 1 175 10.1007/s00018‑024‑05193‑4 38597937
    [Google Scholar]
  37. Li H. Zhang H. Wang G. Chen Z. Pan Y. LncRNA LBX2-AS1 facilitates abdominal aortic aneurysm through miR-4685-5p/LBX2 feedback loop. Biomed. Pharmacother. 2020 129 109904 10.1016/j.biopha.2020.109904 32559617
    [Google Scholar]
  38. Hu M. Yuan X. Liu Y. Tang S. Miao J. Zhou Q. Chen S. IL-1β-induced NF-κB activation down-regulates miR-506 expression to promotes osteosarcoma cell growth through JAG1. Biomed. Pharmacother. 2017 95 1147 1155 10.1016/j.biopha.2017.08.120 28926924
    [Google Scholar]
  39. Yang H. He C. Bi Y. Zhu X. Deng D. Ran T. Ji X. Synergistic effect of VEGF and SDF-1α in endothelial progenitor cells and vascular smooth muscle cells. Front. Pharmacol. 2022 13 914347 10.3389/fphar.2022.914347 35910392
    [Google Scholar]
  40. Chen S. Chen Y. Yu L. Hu X. YTHDC1 inhibits cell proliferation and angiogenesis in cervical cancer by regulating m6A modification of SOCS4 mRNA. Mol. Cell. Toxicol. 2024 20 3 533 540 10.1007/s13273‑023‑00360‑3
    [Google Scholar]
  41. Jiang C. Xie N. Sun T. Ma W. Zhang B. Li W. Xanthohumol inhibits TGF-β1-induced cardiac fibroblasts activation via mediating PTEN/Akt/mTOR signaling pathway. Drug Des. Devel. Ther. 2020 14 5431 5439 10.2147/DDDT.S282206 33324040
    [Google Scholar]
  42. He J. Feng X. Liu Y. Wang Y. Ge C. Liu S. Jiang Y. Graveoline attenuates D-GalN/LPS-induced acute liver injury via inhibition of JAK1/STAT3 signaling pathway. Biomed. Pharmacother. 2024 177 117163 10.1016/j.biopha.2024.117163 39018876
    [Google Scholar]
  43. Chen B. Li Y. Liu Y. Xu Z. circLRP6 regulates high glucose‐induced proliferation, oxidative stress, ECM accumulation, and inflammation in mesangial cells. J. Cell. Physiol. 2019 234 11 21249 21259 10.1002/jcp.28730 31087368
    [Google Scholar]
  44. Welden J.R. Stamm S. Pre-mRNA structures forming circular RNAs. Gene Regulatory Mechanisms 2019 1862 11-12 194410 31421281
    [Google Scholar]
  45. Li D. Yang Y. Li Z.Q. Li L.C. Zhu X.H. Circular RNAs. Chin. Med. J. 2019 132 20 2457 2464 10.1097/CM9.0000000000000465 31651510
    [Google Scholar]
  46. Chen X. Zhou M. Yant L. Huang C. Circular RNA in disease: Basic properties and biomedical relevance. Wiley Interdiscip. Rev. RNA 2022 13 6 e1723 10.1002/wrna.1723 35194939
    [Google Scholar]
  47. Wu M. Xun M. Chen Y. Circular RNAs: Regulators of vascular smooth muscle cells in cardiovascular diseases. J. Mol. Med. 2022 100 4 519 535 10.1007/s00109‑022‑02186‑3 35254452
    [Google Scholar]
  48. Misir S. Wu N. Yang B.B. Specific expression and functions of circular RNAs. Cell Death Differ. 2022 29 3 481 491 10.1038/s41418‑022‑00948‑7 35169296
    [Google Scholar]
  49. Choke E. Cockerill G.W. Dawson J. Chung Y.L. Griffiths J. Wilson R.W. Loftus I.M. Thompson M.M. Hypoxia at the site of abdominal aortic aneurysm rupture is not associated with increased lactate. Ann. N. Y. Acad. Sci. 2006 1085 1 306 310 10.1196/annals.1383.005 17182947
    [Google Scholar]
  50. Van Vickle-Chavez S.J. Tung W.S. Absi T.S. Ennis T.L. Mao D. Cobb J.P. Thompson R.W. Temporal changes in mouse aortic wall gene expression during the development of elastase-induced abdominal aortic aneurysms. J. Vasc. Surg. 2006 43 5 1010 1020 10.1016/j.jvs.2006.01.004 16678698
    [Google Scholar]
  51. Yuan M. Wang L. Wang H. Chen Y. Guan H. Research progress on the role of HIF-1α in atherosclerosis. Chin. J. Arterioscler. 2023 31 815 820
    [Google Scholar]
  52. He A.T. Liu J. Li F. Yang B.B. Targeting circular RNAs as a therapeutic approach: Current strategies and challenges. Signal Transduct. Target. Ther. 2021 6 1 185 10.1038/s41392‑021‑00569‑5 34016945
    [Google Scholar]
/content/journals/cpb/10.2174/0113892010327133250424073216
Loading
/content/journals/cpb/10.2174/0113892010327133250424073216
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.


  • Article Type:
    Research Article
Keywords: progression ; CircRNA ; HIF-1α ; miR-29a-3p ; abdominal aortic aneurysm ; CircLRP6
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test