Skip to main content
SpringerLink
Log in

Hydroxysafflor Yellow A Inhibits Pyroptosis and Protecting HUVECs from OGD/R via NLRP3/Caspase-1/GSDMD Pathway

  • Original Article
  • Published:
Chinese Journal of Integrative Medicine Aims and scope Submit manuscript

Abstract

Objective

To observe the protective effect and mechanism of hydroxyl safflower yellow A (HSYA) from myocardial ischemia-reperfusion injury on human umbilical vein endothelial cells (HUVECs).

Methods

HUVECs were treated with oxygen-glucose deprivation reperfusion (OGD/R) to simulate the ischemia reperfusion model, and cell counting kit-8 was used to detect the protective effect of different concentrations (1.25–160 µ mol/L) of HSYA on HUVECs after OGD/R. HSYA 80 µ mol/L was used for follow-up experiments. The contents of inflammatory cytokines interleukin (IL)-18, IL-1 β, monocyte chemotactic protein 1 (MCP-1), tumor necrosis factor α (TNF-α) and IL-6 before and after administration were measured by enzyme-linked immunosorbent assay. The protein expressions of toll-like receptor, NOD-like receptor containing pyrin domain 3 (NLRP3), gasdermin D (GSDMD) and GSDMD-N-terminal domain (GSDMD-N) before and after administration were detected by Western blot. NLRP3 inflammasome inhibitor cytokine release inhibitory drug 3 sodium salt (CRID3 sodium salt, also known as MCC950) and agonist were added, and the changes of NLRP3, cysteine-aspartic acid protease 1 (Caspase-1), GSDMD and GSDMD-N protein expressions were detected by Western blot.

Results

HSYA inhibited OGD/R-induced inflammation and significantly decreased the contents of inflammatory cytokines IL-18, IL-1 β, MCP-1, TNF-α and IL-6 (P<0.01 or P<0.05). At the same time, by inhibiting NLRP3/Caspase-1/GSDMD pathway, HSYA can reduce the occurrence of pyroptosis after OGD/R and reduce the expression of NLRP3, Caspase-1, GSDMD and GSDMD-N proteins (P<0.01).

Conclusions

The protective effect of HSYA on HUVECs after OGD/R is related to down-regulating the expression of NLRP3 inflammasome and inhibiting pyroptosis.

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

Similar content being viewed by others

References

  1. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 2007;357:1121–1135.

    Article  CAS  PubMed  Google Scholar 

  2. Hausenloy DJ, Yellon DM. Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J Clin Invest 2013;123:92–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Turer AT, Hill JA. Pathogenesis of myocardial ischemia-reperfusion injury and rationale for therapy. Am J Cardiol 2010;106:360–368.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Pober JS, Sessa WC. Evolving functions of endothelial cells in inflammation. Nat Rev Immunol 2007;7:803–815.

    Article  CAS  PubMed  Google Scholar 

  5. Sturtzel C. Endothelial cells. Adv Exp Med Biol 2017;1003:71–91.

    Article  CAS  PubMed  Google Scholar 

  6. Koch A, Bingold TM, Oberländer J, Sack FU, Otto HF, Hagl S, et al. Capillary endothelia and cardiomyocytes differ in vulnerability to ischemia/reperfusion during clinical heart transplantation. Eur J Cardiothorac Surg 2001;20:996–1001.

    Article  CAS  PubMed  Google Scholar 

  7. Schroder K, Tschopp J. The inflammasomes. Cell 2010;140:821–832.

    Article  CAS  PubMed  Google Scholar 

  8. Swanson KV, Deng M, Ting JP. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol 2019;19:477–489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Shen S, Wang Z, Sun H, Ma L. Role of NLRP3 inflammasome in myocardial ischemia-reperfusion injury and ventricular remodeling. Med Sci Monit 2022;28:e934255.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Lu Q, Xu J, Li Q, Wu W, Wu Y, Xie J, et al. Therapeutic efficacy and safety of safflower injection in the treatment of acute coronary syndrome. Evid Based Complement Alternat Med 2021;2021:6617772.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Zhai J, Ji Z, Jin X, Du X, Cao L, Zheng W. Meta-analysis of the effect of Honghua Injection in the treatment of coronary heart disease angina pectoris. Evid Based Complement Alternat Med 2022;2022:4537043.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Liang MM, Li SF, Wang KH, Zhang LW. Biological activity and hydroxy safflor yellow A content of intermediates in preparation of Safflower Injection. China J Chin Mater Med (Chin) 2018;43:4850–4854.

    Google Scholar 

  13. Hu T, Wei G, Xi M, Yan J, Wu X, Wang Y, et al. Synergistic cardioprotective effects of Danshensu and hydroxysafflor yellow A against myocardial ischemia-reperfusion injury are mediated through the Akt/Nrf2/HO-1 pathway. Int J Mol Med 2016;38:83–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ye JX, Wang M, Wang RY, Liu HT, Qi YD, Fu JH, et al. Hydroxysafflor yellow A inhibits hypoxia/reoxygenation-induced cardiomyocyte injury via regulating the AMPK/NLRP3 inflammasome pathway. Int Immunopharmacol 2020;82:106316.

    Article  CAS  PubMed  Google Scholar 

  15. Ye J, Wang R, Wang M, Fu J, Zhang Q, Sun G, et al. Hydroxysafflor yellow A ameliorates myocardial ischemia/reperfusion injury by suppressing calcium overload and apoptosis. Oxid Med Cell Longev 2021;2021:6643615.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Liu YN, Zhou ZM, Chen P. Evidence that hydroxysafflor yellow A protects the heart against ischaemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening. Clin Exp Pharmacol Physiol 2008;35:211–216.

    Article  ADS  CAS  PubMed  Google Scholar 

  17. Liu SX, Zhang Y, Wang YF, Li XC, Xiang MX, Bian C, et al. Upregulation of heme oxygenase-1 expression by hydroxysafflor yellow A conferring protection from anoxia/reoxygenation-induced apoptosis in H9c2 cardiomyocytes. Int J Cardiol 2012;160:95–101.

    Article  PubMed  Google Scholar 

  18. Del Re DP, Amgalan D, Linkermann A, Liu Q, Kitsis RN. Fundamental mechanisms of regulated cell death and implications for heart disease. Physiol Rev 2019;99:1765–1817.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zheng Y, Xu X, Chi F, Cong N. Pyroptosis: a newly discovered therapeutic target for ischemia-reperfusion injury. Biomolecules 2022;12:1625.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Toldo S, Mauro AG, Cutter Z, Abbate A. Inflammasome, pyroptosis, and cytokines in myocardial ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 2018;315:H1553–H1568.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bai B, Yang Y, Wang Q, Li M, Tian C, Liu Y, et al. NLRP3 inflammasome in endothelial dysfunction. Cell Death Dis 2020;11:776.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bai R, Lang Y, Shao J, Deng Y, Refuhati R, Cui L. The role of NLRP3 inflammasome in cerebrovascular diseases pathology and possible therapeutic targets. ASN Neuro 2021;13:17590914211018100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. García JA, Volt H, Venegas C, Doerrier C, Escames G, López LC, et al. Disruption of the NF-κ B/NLRP3 connection by melatonin requires retinoid-related orphan receptor-a and blocks the septic response in mice. FASEB J 2015;29:3863–3875.

    Article  PubMed  Google Scholar 

  24. Cai SM, Yang RQ, Li Y, Ning ZW, Zhang LL, Zhou GS, et al. Angiotensin-(1–7) improves liver fibrosis by regulating the NLRP3 inflammasome via redox balance modulation. Antioxid Redox Sign 2016;24:795–812.

    Article  CAS  Google Scholar 

  25. Zhong Z, Umemura A, Sanchez-Lopez E, Liang S, Shalapour S, Wong J, et al. NF-κB restricts inflammasome activation via elimination of damaged mitochondria. Cell 2016;164:896–910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Liu Y, Zhang J, Zhang D, Yu P, Zhang J, Yu S. Research progress on the role of pyroptosis in myocardial ischemia-reperfusion injury. Cells 2022;11:3271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Valikeserlis I, Athanasiou AA, Stakos D. Cellular mechanisms and pathways in myocardial reperfusion injury. Coron Artery Dis 2021;32:567–577.

    Article  PubMed  Google Scholar 

  28. Singhal AK, Symons JD, Boudina S, Jaishy B, Shiu YT, Role of endothelial cells in myocardial ischemia-reperfusion injury. Vasc Dis Prev 2010;7:1–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Davidson SM, Duchen MR. Endothelial mitochondria: contributing to vascular function and disease. Circ Res 2007;100:1128–41.

    Article  CAS  PubMed  Google Scholar 

  30. Quintero M, Colombo SL, Godfrey A, Moncada S. Mitochondria as signaling organelles in the vascular endothelium. Proc Natl Acad Sci U S A 2006;103:5379–5384.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  31. Krüger-Genge A, Blocki A, Franke RP, Jung F. Vascular endothelial cell biology: an update. Int J Mol Sci 2019;20:4411.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Chen Z, Martin M, Li Z, Shyy JY. Endothelial dysfunction: the role of sterol regulatory element-binding protein-induced NOD-like receptor family pyrin domain-containing protein 3 inflammasome in atherosclerosis. Curr Opin Lipidol 2014;25:339–349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Deretic V, Levine B. Autophagy balances inflammation in innate immunity. Autophagy 2018;14:243–251.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chang X, Liu R, Li R, Peng Y, Zhu P, Zhou H. Molecular mechanisms of mitochondrial quality control in ischemic cardiomyopathy. Int J Biol Sci 2023;19:426–448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yue RC, Lu SZ, Luo Y, Wang T, Liang H, Zeng J, et al. Calpain silencing alleviates myocardial ischemia-reperfusion injury through the NLRP3/ASC/caspase-1 axis in mice. Life Sci 2019;233:116631.

    Article  CAS  PubMed  Google Scholar 

  36. Li C, Song H, Chen C, Chen S, Zhang Q, Liu D, et al. LncRNA PVT1 knockdown ameliorates myocardial ischemia reperfusion damage via suppressing gasdermin D-mediated pyroptosis in cardiomyocytes. Front Cardiovasc Med 2021;8:747802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Huang Y, Xu W, Zhou R. NLRP3 inflammasome activation and cell death. Cell Mol Immunol 2021;18:2114–2127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China

    Fan Guo, Xiao Han, Yue You, Shu-juan Xu, Ye-hao Zhang, Yuan-yuan Chen, Gao-jie Xin, Zi-xin Liu, Jun-guo Ren, Ce Cao, Ling-mei Li & Jian-hua Fu

  2. Beijing Key Laboratory of Chinese Materia Pharmacology, Beijing, 100091, China

    Fan Guo, Xiao Han, Yue You, Shu-juan Xu, Ye-hao Zhang, Yuan-yuan Chen, Gao-jie Xin, Zi-xin Liu, Jun-guo Ren, Ce Cao, Ling-mei Li & Jian-hua Fu

  3. Department of Central Laboratory, Kunshan Hospital of Chinese Medicine, Kunshan, Jiangsu Province, 215300, China

    Ling-mei Li

Authors
  1. Fan Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiao Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yue You
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shu-juan Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ye-hao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuan-yuan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gao-jie Xin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zi-xin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jun-guo Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ce Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ling-mei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jian-hua Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Li LM: conceptualization, funding acquisition, project administration and investigation; Guo F: conceptualization, visualization, writing—original draft, formal analysis, and writing—review & editing; Han X, Zhang YH, Ren JG: resources; You Y, Xu SJ, Chen YY, Xin GJ, Liu ZX, Cao C: investigation; Fu JH: conceptualization, funding acquisition, and supervision. Fu JH and Li LM contributed equally to this study.

Corresponding author

Correspondence to Ling-mei Li.

Ethics declarations

There is no potential conflict of interest among authors.

Additional information

Supported by the Youth Planning Project of Beijing Science and Technology Development Fund for Chinese Medicine (No. QN-2020-14), Innovation Fund of China Academy of Chinese Medical Sciences (No. CI2021A00912), and Scientific Fund of National Clinical Research Center for Chinese Medicine Cardiology (No. CMC2022005)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guo, F., Han, X., You, Y. et al. Hydroxysafflor Yellow A Inhibits Pyroptosis and Protecting HUVECs from OGD/R via NLRP3/Caspase-1/GSDMD Pathway. Chin. J. Integr. Med. (2024). https://doi.org/10.1007/s11655-023-3716-y

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11655-023-3716-y

Keywords

Search

Navigation