Skip to main content

Advertisement

SpringerLink
Log in

Ligustrazine Protects Homocysteine-Induced Apoptosis in Human Umbilical Vein Endothelial Cells by Modulating Mitochondrial Dysfunction

  • Original Article
  • Published:
Journal of Cardiovascular Translational Research Aims and scope Submit manuscript

Abstract

Ligustrazine is one of the alkaloid compounds isolated from the traditional Chinese herb, which shows protective effects on cardiovascular disorders. High homocysteine (Hcy) level can predict cardiovascular-related events including death. In this study, we used Hcy to stimulate the human umbilical vein endothelial cells (HUVECs) and investigated the protective effect of ligustrazine on endothelial dysfunction by assessing the cell apoptosis, oxidative damage, mitochondrial dysfunction, and the potential molecular pathways. Our results clearly showed that ligustrazine increased HUVEC cell viability, decreased the dehydrogenase (LDH) level, and inhibited HUVEC apoptosis, which was associated with the attenuation of attenuated oxidative damage. The mitochondrial-dependent pathway was closely related in the regulation of ligustrazine, reflected by the attenuated mitochondrial membrane potential change and decreased cytochrome c release from the mitochondria to the cytosol. Ligustrazine may protect Hcy-induced apoptosis in HUVECs by attenuating oxidative damage and modulating mitochondrial dysfunction.

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

Similar content being viewed by others

References

  1. Clarke, R., Daly, L., Robinson, K., Naughten, E., Cahalane, S., Fowler, B., et al. (1991). Hyperhomocysteinemia: an independent risk factor for vascular disease. The New England Journal of Medicine, 324(17), 1149–1155. https://doi.org/10.1056/nejm199104253241701.

    Article  CAS  PubMed  Google Scholar 

  2. Marasini, B., Massarotti, M., & Biondi, M. L. (2002). Homocysteine and vascular diseases. Circulation, 106(7), e33.

    Article  PubMed  Google Scholar 

  3. Nygard, O., Nordrehaug, J. E., Refsum, H., Ueland, P. M., Farstad, M., & Vollset, S. E. (1997). Plasma homocysteine levels and mortality in patients with coronary artery disease. The New England Journal of Medicine, 337(4), 230–236. https://doi.org/10.1056/nejm199707243370403.

    Article  CAS  PubMed  Google Scholar 

  4. Wu, X., Zhang, L., Miao, Y., Yang, J., Wang, X., Wang, C. C., et al. (2018). Homocysteine causes vascular endothelial dysfunction by disrupting endoplasmic reticulum redox homeostasis. Redox Biology, 20, 46–59. https://doi.org/10.1016/j.redox.2018.09.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Shi, W., Wang, X., Shih, D. M., Laubach, V. E., Navab, M., & Lusis, A. J. (2002). Paradoxical reduction of fatty streak formation in mice lacking endothelial nitric oxide synthase. Circulation, 105(17), 2078–2082.

    Article  CAS  PubMed  Google Scholar 

  6. Liu, C., & Huang, Y. (2016). Chinese herbal medicine on cardiovascular diseases and the mechanisms of action. Frontiers in Pharmacology, 7, 469. https://doi.org/10.3389/fphar.2016.00469.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chang, Y., Hsiao, G., Chen, S. H., Chen, Y. C., Lin, J. H., Lin, K. H., et al. (2007). Tetramethylpyrazine suppresses HIF-1alpha, TNF-alpha, and activated caspase-3 expression in middle cerebral artery occlusion-induced brain ischemia in rats. Acta Pharmacologica Sinica, 28(3), 327–333. https://doi.org/10.1111/j.1745-7254.2007.00514.x.

    Article  CAS  PubMed  Google Scholar 

  8. Fan, L. H., Wang, K. Z., Cheng, B., Wang, C. S., & Dang, X. Q. (2006). Anti-apoptotic and neuroprotective effects of tetramethylpyrazine following spinal cord ischemia in rabbits. BMC Neuroscience, 7, 48. https://doi.org/10.1186/1471-2202-7-48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wu, H. J., Hao, J., Wang, S. Q., Jin, B. L., & Chen, X. B. (2012). Protective effects of ligustrazine on TNF-alpha-induced endothelial dysfunction. European Journal of Pharmacology, 674(2–3), 365–369. https://doi.org/10.1016/j.ejphar.2011.10.046.

    Article  CAS  PubMed  Google Scholar 

  10. Yang, C., Xu, Y., Zhou, H., Yang, L., Yu, S., Gao, Y., et al. (2016). Tetramethylpyrazine protects CoCl2-induced apoptosis in human umbilical vein endothelial cells by regulating the PHD2/HIF/1alpha-VEGF pathway. Molecular Medicine Reports, 13(2), 1287–1296. https://doi.org/10.3892/mmr.2015.4679.

    Article  CAS  PubMed  Google Scholar 

  11. Tveden-Nyborg, P., Bergmann, T. K., & Lykkesfeldt, J. (2018). Basic & clinical pharmacology & toxicology policy for experimental and clinical studies. Basic & Clinical Pharmacology & Toxicology, 123(3), 233–235. https://doi.org/10.1111/bcpt.13059.

    Article  CAS  Google Scholar 

  12. Deshmukh, M., & Johnson, E. M., Jr. (1998). Evidence of a novel event during neuronal death: development of competence-to-die in response to cytoplasmic cytochrome c. Neuron, 21(4), 695–705.

    Article  CAS  PubMed  Google Scholar 

  13. Rajendran, P., Rengarajan, T., Thangavel, J., Nishigaki, Y., Sakthisekaran, D., Sethi, G., et al. (2013). The vascular endothelium and human diseases. International Journal of Biological Sciences, 9(10), 1057–1069. https://doi.org/10.7150/ijbs.7502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ansar, S., Koska, J., & Reaven, P. D. (2011). Postprandial hyperlipidemia, endothelial dysfunction and cardiovascular risk: focus on incretins. Cardiovascular Diabetology, 10, 61. https://doi.org/10.1186/1475-2840-10-61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Feletou, M., & Vanhoutte, P. M. (2006). Endothelium-derived hyperpolarizing factor: where are we now? Arteriosclerosis, Thrombosis, and Vascular Biology, 26(6), 1215–1225. https://doi.org/10.1161/01.ATV.0000217611.81085.c5.

    Article  CAS  PubMed  Google Scholar 

  16. Suwaidi, J. A., Hamasaki, S., Higano, S. T., Nishimura, R. A., Holmes, D. R., Jr., & Lerman, A. (2000). Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation, 101(9), 948–954.

    Article  CAS  PubMed  Google Scholar 

  17. Ross, R. (1999). Atherosclerosis--an inflammatory disease. The New England Journal of Medicine, 340(2), 115–126. https://doi.org/10.1056/nejm199901143400207.

    Article  CAS  PubMed  Google Scholar 

  18. Hofmann, M. A., Lalla, E., Lu, Y., Gleason, M. R., Wolf, B. M., Tanji, N., et al. (2001). Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. The Journal of Clinical Investigation, 107(6), 675–683. https://doi.org/10.1172/jci10588.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhang, Z., Wei, C., Zhou, Y., Yan, T., Wang, Z., Li, W., et al. (2017). Homocysteine induces apoptosis of human umbilical vein endothelial cells via mitochondrial dysfunction and endoplasmic reticulum stress. Oxidative Medicine and Cellular Longevity, 2017, 5736506. https://doi.org/10.1155/2017/5736506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Peng, W., Hucks, D., Priest, R. M., Kan, Y. M., & Ward, J. P. (1996). Ligustrazine-induced endothelium-dependent relaxation in pulmonary arteries via an NO-mediated and exogenous L-arginine-dependent mechanism. British Journal of Pharmacology, 119(5), 1063–1071. https://doi.org/10.1111/j.1476-5381.1996.tb15778.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhao, T., Fu, Y., Sun, H., & Liu, X. (2018). Ligustrazine suppresses neuron apoptosis via the Bax/Bcl-2 and caspase-3 pathway in PC12 cells and in rats with vascular dementia. IUBMB Life, 70(1), 60–70. https://doi.org/10.1002/iub.1704.

    Article  CAS  PubMed  Google Scholar 

  22. Chen, J., Chen, J., Wang, X., Wang, C., Cao, W., Zhao, Y., et al. (2016). Ligustrazine alleviates acute pancreatitis by accelerating acinar cell apoptosis at early phase via the suppression of p38 and Erk MAPK pathways. Biomedicine & Pharmacotherapy, 82, 1–7. https://doi.org/10.1016/j.biopha.2016.04.048.

    Article  CAS  Google Scholar 

  23. Pan, J., Shang, J. F., Jiang, G. Q., & Yang, Z. X. (2015). Ligustrazine induces apoptosis of breast cancer cells in vitro and in vivo. Journal of Cancer Research and Therapeutics, 11(2), 454–458. https://doi.org/10.4103/0973-1482.147378.

    Article  CAS  PubMed  Google Scholar 

  24. Yip, K. W., & Reed, J. C. (2008). Bcl-2 family proteins and cancer. Oncogene, 27(50), 6398–6406. https://doi.org/10.1038/onc.2008.307.

    Article  CAS  PubMed  Google Scholar 

  25. Xu, Z., Lu, G., & Wu, F. (2009). Simvastatin suppresses homocysteine-induced apoptosis in endothelial cells: roles of caspase-3, cIAP-1 and cIAP-2. Hypertension Research, 32(5), 375–380. https://doi.org/10.1038/hr.2009.24.

    Article  CAS  PubMed  Google Scholar 

  26. Tait, S. W., & Green, D. R. (2010). Mitochondria and cell death: outer membrane permeabilization and beyond. Nature Reviews. Molecular Cell Biology, 11(9), 621–632. https://doi.org/10.1038/nrm2952.

    Article  CAS  PubMed  Google Scholar 

  27. Boatright, K. M., & Salvesen, G. S. (2003). Mechanisms of caspase activation. Current Opinion in Cell Biology, 15(6), 725–731.

    Article  CAS  PubMed  Google Scholar 

  28. Saleh, F. A., Whyte, M., & Genever, P. G. (2011). Effects of endothelial cells on human mesenchymal stem cell activity in a three-dimensional in vitro model. European Cells & Materials, 22, 242–257 discussion 257.

    Article  CAS  Google Scholar 

Download references

Funding

The study was supported by the Natural Science Foundation of China (81770353).

Author information

Authors and Affiliations

  1. Department of Clinical Laboratory Center, Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, China

    Xuesong Fan, Jianxun He, Lei Zhang, Xiaoli Zeng, Yuan Gui, Qi Sun, Yang Song & Hui Yuan

  2. Center for Pediatric Cardiac Surgery, National Center for Cardiovascular Diseases and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China

    Enshi Wang

Authors
  1. Xuesong Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Enshi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jianxun He
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaoli Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuan Gui
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qi Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yang Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hui Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hui Yuan.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Research Involving Human Participants and/or Animals

The study does not contain any research involving Human Participants and/or Animals.

Informed Consent

Not applicable.

Additional information

Associate Editor Adrian Chester oversaw the review of this article.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Figure 6

Effects of Ligustrazine on NO production in response to homocysteine. a, NO assay kit was used to measure the dose-dependent effects of homocysteine treatment for 24 h on NO production in HUVECs culture medium. b, Effects of different dose of ligustrazine on NO production in HUVECs culture medium in response to 4 mM homocysteine. Data are presented as mean ± SD. *p < 0.05, **p < 0.01 and ***p < 0.001 compared to control group, #p < 0.05 and ##p < 0.01 compared to only Hcy treated group (one-way ANOVA). (PNG 33 kb)

High Resolution (TIF 58 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fan, X., Wang, E., He, J. et al. Ligustrazine Protects Homocysteine-Induced Apoptosis in Human Umbilical Vein Endothelial Cells by Modulating Mitochondrial Dysfunction. J. of Cardiovasc. Trans. Res. 12, 591–599 (2019). https://doi.org/10.1007/s12265-019-09900-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12265-019-09900-6

Keywords

Search

Navigation