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KLF15 Transcriptionally Activates ATG14 to Promote Autophagy and Attenuate Damage of ox-LDL-Induced HAECs

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Abstract

Kruppel-like factor 15 (KLF15) is involved in many cardiovascular diseases and is abnormally expressed in atherosclerosis (AS), but the regulatory mechanism of KLF15 in AS has not been reported so far. RT-qPCR was used to detect the expression of KLF15 and ATG14 in AS patients. Subsequently, human aortic endothelial cells (HAECs) were induced by oxidized low densitylipoprotein (ox-LDL), and the expression of KLF15 in model cells was detected. KLF15 was overexpressed in cells by lipofection transfection, and then CCK8, flow cytometry, Western blot, ELISA, and related assay kits were used to detect cell viability, apoptosis, inflammatory response as well as oxidative stress, respectively. The targeted regulatory relationship between KLF15 and autophagy-related 14 (ATG14) was detected by ChIP and luciferase reporter assays. Following ATG14 silencing in KLF15-overexpressing cells, immunofluorescence and Western blot were used to detect the autophagy. Finally, after the addition of 3-Methyladenine (3-MA), an autophagy inhibitor, the aforementioned experiments were conducted again to further explore the mechanism. The expression of KLF15 and ATG14 were decreased in AS patients and ox-LDL-induced HAECs. Overexpression of KLF15 protected ox-LDL-induced HAECs from damage, which might be achieved through transcriptional regulation of ATG14. In addition, KLF15 could promote autophagy through transcriptional activation of ATG14. KLF15 transcriptionally activated ATG14 to promote autophagy and attenuate damage of ox-LDL-induced HAECs.

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Data Availability

The datasets used and/or analyzed generated during the current study are available from the corresponding author on reasonable request.

References

  1. Libby, P. (2021). The changing landscape of atherosclerosis. Nature, 592, 524–533.

    Article  CAS  PubMed  Google Scholar 

  2. Soehnlein, O., & Libby, P. (2021). Targeting inflammation in atherosclerosis—From experimental insights to the clinic. Nature Reviews. Drug Discovery, 20, 589–610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Rocha, V. Z., & Libby, P. (2009). Obesity, inflammation, and atherosclerosis. Nature Reviews Cardiology, 6, 399–409.

    Article  CAS  PubMed  Google Scholar 

  4. Gimbrone, M. A., Jr., & Garcia-Cardena, G. (2016). Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circulation Research, 118, 620–636.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Levine, B., & Kroemer, G. (2019). Biological functions of autophagy genes: A disease perspective. Cell, 176, 11–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yuping, Y., Hua, C., & Qing, Z. (2018). Advances in the relationship between Kruppel-like factor 15 and cardiovascular disease research. Cardiovascular Endocrinology & Metabolism, 7, 37–41.

    Article  Google Scholar 

  7. Lu, Y., Zhang, L., Liao, X., Sangwung, P., Prosdocimo, D. A., Zhou, G., Votruba, A. R., Brian, L., Han, Y. J., Gao, H., & Wang, Y. (2013). Kruppel-like factor 15 is critical for vascular inflammation. The Journal of Clinical Investigation, 123, 4232–4241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Liu, B., Xu, L., Yu, X., Li, W., Sun, X., Xiao, S., Guo, M., & Wang, H. (2018). Protective effect of KLF15 on vascular endothelial dysfunction induced by TNFalpha. Molecular Medicine Reports, 18, 1987.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Nègre-Salvayre, A., Augé, N., Camaré, C., Bacchetti, T., Ferretti, G., & Salvayre, R. (2017). Dual signaling evoked by oxidized LDLs in vascular cells. Free Radical Biology & Medicine, 106, 118–133.

    Article  Google Scholar 

  10. Kattoor, A. J., Kanuri, S. H., & Mehta, J. L. (2019). Role of Ox-LDL and LOX-1 in atherogenesis. Current Medicinal Chemistry, 26, 1693–1700.

    Article  CAS  PubMed  Google Scholar 

  11. Wei, X., Lin, H., Zhang, B., Li, M., Chen, Y., Huang, Y., Zhang, J., Yang, Y., Guo, Z., Li, W., & Ye, L. (2021). Phoenixin-20 prevents ox-LDL-induced attachment of monocytes to human aortic endothelial cells (HAECs): A protective implication in atherosclerosis. ACS Chemical Neuroscience, 12, 990–997.

    Article  CAS  PubMed  Google Scholar 

  12. Gao, L., Guo, Y., Liu, X., Shang, D., & Du, Y. (2017). KLF15 protects against isoproterenol-induced cardiac hypertrophy via regulation of cell death and inhibition of Akt/mTOR signaling. Biochemical and Biophysical Research Communications, 487, 22–7.

    Article  CAS  PubMed  Google Scholar 

  13. Wang, Y., Zhang, C. X., Ge, S. L., & Gong, W. H. (2020). CTBP1AS2 inhibits proliferation and induces autophagy in oxLDLstimulated vascular smooth muscle cells by regulating miR1955p/ATG14. International Journal of Molecular Medicine, 46, 839–848.

    Article  PubMed  Google Scholar 

  14. Gui, Y., Zheng, H., & Cao, R. Y. (2022). Foam cells in atherosclerosis: novel insights into its origins, consequences, and molecular mechanisms. Frontiers in Cardiovascular Medicine, 9, 845942.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods (San Diego, Calif), 25, 402–8.

    Article  CAS  PubMed  Google Scholar 

  16. Gao, Y., Li, G., Fan, S., Wei, H., Li, M., & Li, X. (2021). Circ_0093887 upregulates CCND2 and SUCNR1 to inhibit the ox-LDL-induced endothelial dysfunction in atherosclerosis by functioning as a miR-876-3p sponge. Clinical and Experimental Pharmacology and Physiology, 48, 1137–1149.

    Article  CAS  PubMed  Google Scholar 

  17. Xu, X. S., Shao, N., Duan, X. T., Zhang, X., & Zhang, Y. (2018). Tacrolimus alleviates Ox-LDL damage through inducing vascular endothelial autophagy. European Review for Medical and Pharmacological Sciences, 22, 3199–3206.

    PubMed  Google Scholar 

  18. Yu, X. H., Fu, Y. C., Zhang, D. W., Yin, K., & Tang, C. K. (2013). Foam cells in atherosclerosis. Clinica Chimica Acta: International Journal of Clinical Chemistry, 424, 245–52.

    Article  CAS  PubMed  Google Scholar 

  19. Sluiter, T. J., van Buul, J. D., Huveneers, S., Quax, P. H., & de Vries, M. R. (2021). Endothelial barrier function and leukocyte transmigration in atherosclerosis. Biomedicines, 9, 328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wei, Z., Ran, H., & Yang, C. (2020). CircRSF1 contributes to endothelial cell growth, migration and tube formation under ox-LDL stress through regulating miR-758/CCND2 axis. Life Sciences, 259, 118241.

    Article  CAS  PubMed  Google Scholar 

  21. Marchio, P., Guerra-Ojeda, S., Vila, J. M., Aldasoro, M., Victor, V. M., & Mauricio, M. D. (2019). Targeting early atherosclerosis: A focus on oxidative stress and inflammation. Oxidative Medicine and Cellular Longevity, 2019, 8563845.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Wu, M. Y., Li, C. J., Hou, M. F., & Chu, P. Y. (2017). New Insights into the role of inflammation in the pathogenesis of atherosclerosis. International Journal of Molecular Sciences, 18, 2034.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Zhao, X., Chen, L., Wu, J., You, J., Hong, Q., & Ye, F. (2021). Transcription factor KLF15 inhibits the proliferation and migration of gastric cancer cells via regulating the TFAP2A-AS1/NISCH axis. Biology Direct, 16, 21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhao, Y., Song, W., Wang, L., Rane, M. J., Han, F., & Cai, L. (2019). Multiple roles of KLF15 in the heart: Underlying mechanisms and therapeutic implications. Journal of Molecular and Cellular Cardiology, 129, 193–196.

    Article  CAS  PubMed  Google Scholar 

  25. Wang, X. P., Huang, Z., Li, Y. L., Jin, K. Y., Dong, D. J., Wang, J. X., & Zhao, X. F. (2022). Kruppel-like factor 15 integrated autophagy and gluconeogenesis to maintain glucose homeostasis under 20-hydroxyecdysone regulation. PLoS Genetics, 18, e1010229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. De Meyer, G. R., Grootaert, M. O., Michiels, C. F., et al. (2015). Autophagy in vascular disease. Circulation Research, 116, 468–479.

    Article  PubMed  Google Scholar 

  27. Zhang, H., Ge, S., Ni, B., He, K., Zhu, P., Wu, X., & Shao, Y. (2021). Augmenting ATG14 alleviates atherosclerosis and inhibits inflammation via promotion of autophagosome-lysosome fusion in macrophages. Autophagy, 17, 4218–4230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

Scientific research project of Wuxi Municipal Health Commission (M202109).

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Authors and Affiliations

  1. Department of Emergency, Affiliated Hospital of Jiangnan University, No. 1000 Hefeng Road, Wuxi, 214125, Jiangsu, China

    Dong Han, Ming Huang, Zhen Chang & Wei Sun

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  1. Dong Han
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  2. Ming Huang
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  3. Zhen Chang
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  4. Wei Sun
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Correspondence to Wei Sun.

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The present study was approved by the Affiliated hospital of Jiangnan University (Ethics Code: LS2021083).

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Han, D., Huang, M., Chang, Z. et al. KLF15 Transcriptionally Activates ATG14 to Promote Autophagy and Attenuate Damage of ox-LDL-Induced HAECs. Mol Biotechnol 66, 112–122 (2024). https://doi.org/10.1007/s12033-023-00742-x

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  • DOI: https://doi.org/10.1007/s12033-023-00742-x

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