Skip to main content

Advertisement

Log in

Danlou Tablet Protects Against Myocardial Infarction Through Promoting eNOS-Dependent Endothelial Protection and Angiogenesis

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

Abstract

Myocardial infarction (MI) is one of the leading causes of death worldwide. Danlou tablet (Dan) is an effective traditional Chinese medicine for cardiac protection, although the underlying mechanism was not fully understood. In this study, we used a murine MI model and demonstrated that Dan administration effectively attenuated myocardial apoptosis, cardiac remodeling, and heart failure post MI. Dan increased CD31-positive capillaries in MI hearts, and reduced the apoptosis and oxidative stress in human umbilical vein endothelial cells after oxygen–glucose deprivation stress, simultaneously with the activated HIF-1α/VEGFA/eNOS signaling. Moreover, inhibition of eNOS by L-NAME attenuated Dan-induced protection against MI, and abolished its effect in promoting angiogenesis and reducing endothelial apoptosis and oxidative stress. Collectively, Dan is beneficial to promote eNOS-dependent endothelial protection and angiogenesis thus protecting against MI. A deep understanding of Dan-induced protection might help promote clinical usage of Dan in MI treatment.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data Availability

All data generated or analysed during this study are included in this article and its supplementary material files.

References

  1. Jollis JG, Granger CB, Zegre-Hemsey JK, Henry TD, Goyal A, Tamis-Holland JE, et al. Treatment Time and In-Hospital Mortality Among Patients With ST-Segment Elevation Myocardial Infarction, 2018–2021. JAMA. 2022;328(20):2033–40. https://doi.org/10.1001/jama.2022.20149.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Rodriguez-Palomares JF, Gavara J, Ferreira-Gonzalez I, Valente F, Rios C, Rodriguez-Garcia J, et al. Prognostic Value of Initial Left Ventricular Remodeling in Patients With Reperfused STEMI. JACC Cardiovasc Imaging. 2019;12(12):2445–56. https://doi.org/10.1016/j.jcmg.2019.02.025.

    Article  PubMed  Google Scholar 

  3. Badimon L, Borrell M. Microvasculature Recovery by Angiogenesis After Myocardial Infarction. Curr Pharm Des. 2018;24(25):2967–73. https://doi.org/10.2174/1381612824666180629162726.

    Article  CAS  PubMed  Google Scholar 

  4. Qiu Y, Fernandez-Garcia B, Lehmann HI, Li G, Kroemer G, Lopez-Otin C, et al. Exercise sustains the hallmarks of health. J Sport Health Sci. 2023;12(1):8–35. https://doi.org/10.1016/j.jshs.2022.10.003.

    Article  PubMed  Google Scholar 

  5. Liao Z, Chen Y, Duan C, Zhu K, Huang R, Zhao H, et al. Cardiac telocytes inhibit cardiac microvascular endothelial cell apoptosis through exosomal miRNA-21-5p-targeted cdip1 silencing to improve angiogenesis following myocardial infarction. Theranostics. 2021;11(1):268–91. https://doi.org/10.7150/thno.47021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wu X, Reboll MR, Korf-Klingebiel M, Wollert KC. Angiogenesis after acute myocardial infarction. Cardiovasc Res. 2021;117(5):1257–73. https://doi.org/10.1093/cvr/cvaa287.

    Article  CAS  PubMed  Google Scholar 

  7. White PD, Mallory GK, Salcedo-Salgar J. The Speed of Healing of Myocardial Infarcts. Trans Am Clin Climatol Assoc. 1936;52(97–104):1. https://doi.org/10.1016/s0002-8703(39)90845-8.

    Article  Google Scholar 

  8. Wei M, Guo M, Meng X, Li L, Wang H, Zhang M, et al. PPARgamma Mediates the Cardioprotective Roles of Danlou Tablet After Acute Myocardial Ischemia-Reperfusion Injury. Front Cardiovasc Med. 2022;9:858909. https://doi.org/10.3389/fcvm.2022.858909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Liu C, Chen G, Chen Y, Dang Y, Nie G, Wu D, et al. Danlou Tablets Inhibit Atherosclerosis in Apolipoprotein E-Deficient Mice by Inducing Macrophage Autophagy: The Role of the PI3K-Akt-mTOR Pathway. Front Pharmacol. 2021;12:724670. https://doi.org/10.3389/fphar.2021.724670.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Dai X, Chen R, Chen T, Yan H, Wang Y, Zhou K, et al. Danlou Fang reduces microvascular obstruction through the endothelial/inducible nitric oxide synthase pathway in a rat model. J Tradit Chin Med. 2021;41(2):246–53.

    PubMed  Google Scholar 

  11. Wang L, Mao S, Qi JY, Ren Y, Guo XF, Chen KJ, et al. Effect of Danlou Tablet () on peri-procedural myocardial injury among patients undergoing percutaneous coronary intervention for non-ST elevation acute coronary syndrome: A study protocol of a multicenter, randomized, controlled trial. Chin J Integr Med. 2015;21(9):662–6. https://doi.org/10.1007/s11655-015-2284-1.

    Article  PubMed  Google Scholar 

  12. Wang L, Zhao X, Mao S, Liu S, Guo X, Guo L, et al. Efficacy of Danlou Tablet in Patients with Non-ST Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: Results from a Multicentre, Placebo-Controlled, Randomized Trial. Evid Based Complement Alternat Med. 2016;2016:7960503. https://doi.org/10.1155/2016/7960503.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Zhou Q, Deng J, Pan X, Meng D, Zhu Y, Bai Y, et al. Gut microbiome mediates the protective effects of exercise after myocardial infarction. Microbiome. 2022;10(1):82. https://doi.org/10.1186/s40168-022-01271-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wang H, Maimaitiaili R, Yao J, Xie Y, Qiang S, Hu F, et al. Percutaneous Intracoronary Delivery of Plasma Extracellular Vesicles Protects the Myocardium Against Ischemia-Reperfusion Injury in Canis. Hypertension. 2021;78(5):1541–54. https://doi.org/10.1161/HYPERTENSIONAHA.121.17574.

    Article  CAS  PubMed  Google Scholar 

  15. Chung CY, Duchen MR. A Plate Reader-Based Measurement of the Cellular ROS Production Using Dihydroethidium and MitoSOX. Methods Mol Biol. 2022;2497:333–7. https://doi.org/10.1007/978-1-0716-2309-1_24.

    Article  CAS  PubMed  Google Scholar 

  16. Wang H, Shen X, Liu J, Wu C, Gao J, Zhang Z, et al. The effect of exposure time and concentration of airborne PM25 on lung injury in mice: A transcriptome analysis. Redox Biol. 2019;26:101264. https://doi.org/10.1016/j.redox.2019.101264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sulkshane P, Ram J, Thakur A, Reis N, Kleifeld O, Glickman MH. Ubiquitination and receptor-mediated mitophagy converge to eliminate oxidation-damaged mitochondria during hypoxia. Redox Biol. 2021;45:102047. https://doi.org/10.1016/j.redox.2021.102047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kang Z, Jiang W, Luan H, Zhao F, Zhang S. Cornin induces angiogenesis through PI3K-Akt-eNOS-VEGF signaling pathway. Food Chem Toxicol. 2013;58:340–6. https://doi.org/10.1016/j.fct.2013.05.017.

    Article  CAS  PubMed  Google Scholar 

  19. Nguyen H, Koh JY, Li H, Islas-Robles A, Meda Venkata SP, Wang JM, et al. A novel imidazolinone metformin-methylglyoxal metabolite promotes endothelial cell angiogenesis via the eNOS/HIF-1alpha pathway. FASEB J. 2021;35(7):e21645. https://doi.org/10.1096/fj.202002674RR.

    Article  CAS  PubMed  Google Scholar 

  20. LeBlanc AJ, Krishnan L, Sullivan CJ, Williams SK, Hoying JB. Microvascular repair: post-angiogenesis vascular dynamics. Microcirculation. 2012;19(8):676–95. https://doi.org/10.1111/j.1549-8719.2012.00207.x.

    Article  PubMed  Google Scholar 

  21. Qi JY, Wang L, Gu DS, Guo LH, Zhu W, Zhang MZ. Protective Effects of Danlou Tablet () against Murine Myocardial Ischemia and Reperfusion Injury In Vivo. Chin J Integr Med. 2018;24(8):613–20. https://doi.org/10.1007/s11655-016-2448-7.

    Article  PubMed  Google Scholar 

  22. Wang SH, Wang J, Li J. Efficacy assessment of treating patients with coronary heart disease angina of phlegm and stasis mutual obstruction syndrome by Danlou tablet. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2012;32(8):1051–5.

    PubMed  Google Scholar 

  23. Guo LL, Wang J, Lin F, He YX. Effect of danlou tablet on arrhythmia model rats induced by transient myocardial ischemia/ reperfusion. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2014;34(9):1125–9.

    PubMed  Google Scholar 

  24. Chen J, Cai HW, Miao J, Xu XM, Mao W. Danlou Tablet Fought against Inflammatory Reaction in Atherosclerosis Rats with Intermingled Phlegm and Blood Stasis Syndrome and Its Mechanism Study. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2016;36(6):703–8.

    PubMed  Google Scholar 

  25. Gao LN, Zhou X, Lu YR, Li K, Gao S, Yu CQ, et al. Dan-Lou Prescription Inhibits Foam Cell Formation Induced by ox-LDL via the TLR4/NF-kappaB and PPARgamma Signaling Pathways. Front Physiol. 2018;9:590. https://doi.org/10.3389/fphys.2018.00590.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Zhao X, Chen Y, Li L, Zhai J, Yu B, Wang H, et al. Effect of DLT-SML on Chronic Stable Angina Through Ameliorating Inflammation, Correcting Dyslipidemia, and Regulating Gut Microbiota. J Cardiovasc Pharmacol. 2021;77(4):458–69. https://doi.org/10.1097/FJC.0000000000000970.

    Article  CAS  PubMed  Google Scholar 

  27. Li Z, Yang L, Liu Y, Xu H, Wang S, Liu Y, et al. Anti-inflammatory and antioxidative effects of Dan-Lou tablets in the treatment of coronary heart disease revealed by metabolomics integrated with molecular mechanism studies. J Ethnopharmacol. 2019;240:111911. https://doi.org/10.1016/j.jep.2019.111911.

    Article  PubMed  Google Scholar 

  28. Li L, Qi W, Zhu Y, Yin M, Chen C, Wei M, et al. Danlou Tablet Protects Against Cardiac Remodeling and Dysfunction after Myocardial Ischemia/Reperfusion Injury through Activating AKT/FoxO3a Pathway. J Cardiovasc Transl Res (2023)https://doi.org/10.1007/s12265-023-10365-x

  29. Shoeibi S, Mozdziak P, Mohammadi S. Important signals regulating coronary artery angiogenesis. Microvasc Res. 2018;117:1–9. https://doi.org/10.1016/j.mvr.2017.12.002.

    Article  CAS  PubMed  Google Scholar 

  30. Sun J, Shen H, Shao L, Teng X, Chen Y, Liu X, et al. HIF-1alpha overexpression in mesenchymal stem cell-derived exosomes mediates cardioprotection in myocardial infarction by enhanced angiogenesis. Stem Cell Res Ther. 2020;11(1):373. https://doi.org/10.1186/s13287-020-01881-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Weijts BG, Bakker WJ, Cornelissen PW, Liang KH, Schaftenaar FH, Westendorp B, et al. E2F7 and E2F8 promote angiogenesis through transcriptional activation of VEGFA in cooperation with HIF1. EMBO J. 2012;31(19):3871–84. https://doi.org/10.1038/emboj.2012.231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhou C, Kuang Y, Li Q, Duan Y, Liu X, Yue J, et al. Endothelial S1pr2 regulates post-ischemic angiogenesis via AKT/eNOS signaling pathway. Theranostics. 2022;12(11):5172–88. https://doi.org/10.7150/thno.71585.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang L, Wu T, Si C, Wang H, Yue K, Shang S, et al. Danlou Tablet Activates Autophagy of Vascular Adventitial Fibroblasts Through PI3K/Akt/mTOR to Protect Cells From Damage Caused by Atherosclerosis. Front Pharmacol. 2021;12:730525. https://doi.org/10.3389/fphar.2021.730525.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tang JJ, Li GX, Liu ZG, Yi R, Yu D, Zhang YB, et al. Danlou Tablet Improves Chronic Intermittent Hypoxia-Induced Dyslipidemia and Arteriosclerosis by HIF-1alpha-Angptl4 mRNA Signaling Pathway. Chin J Integr Med. 2022;28(6):509–17. https://doi.org/10.1007/s11655-020-3255-8.

    Article  CAS  PubMed  Google Scholar 

  35. Jung B, Obinata H, Galvani S, Mendelson K, Ding BS, Skoura A, et al. Flow-regulated endothelial S1P receptor-1 signaling sustains vascular development. Dev Cell. 2012;23(3):600–10. https://doi.org/10.1016/j.devcel.2012.07.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Michaud MD, Robitaille GA, Gratton JP, Richard DE. Sphingosine-1-phosphate: a novel nonhypoxic activator of hypoxia-inducible factor-1 in vascular cells. Arterioscler Thromb Vasc Biol. 2009;29(6):902–8. https://doi.org/10.1161/ATVBAHA.109.185280.

    Article  CAS  PubMed  Google Scholar 

  37. Thibeault S, Rautureau Y, Oubaha M, Faubert D, Wilkes BC, Delisle C, et al. S-nitrosylation of beta-catenin by eNOS-derived NO promotes VEGF-induced endothelial cell permeability. Mol Cell. 2010;39(3):468–76. https://doi.org/10.1016/j.molcel.2010.07.013.

    Article  CAS  PubMed  Google Scholar 

  38. Fraisl P. Crosstalk between oxygen- and nitric oxide-dependent signaling pathways in angiogenesis. Exp Cell Res. 2013;319(9):1331–9. https://doi.org/10.1016/j.yexcr.2013.02.010.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the grants from National Key Research and Development Program of China (2017YFC1700401 to YH Bei), National Natural Science Foundation of China (81970335 and 82170285 to YH Bei, 82000253 to HY Wang), the Sailing Program from Science and Technology Commission of Shanghai (20YF1414000 to HY Wang), the grant from Science and Technology Commission of Shanghai Municipality (23010500300 and 21SQBS00100 to YH Bei, 23ZR1422900 to HY Wang), and “Chenguang Program” of Shanghai Education Development Foundation and Shanghai Municipal Education Commission (20CG46 to HY Wang).

Author information

Authors and Affiliations

Authors

Contributions

Y Zhu, Y Chai, Z Su, W Qi, M Yin, L Li, M Wei, and J Ge performed the experiments and analyzed the data. Y Bei and H Wang designed the study, instructed the experiments, and drafted the manuscript. Z Jiao provided technical support and instructed the experiments for the work. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Hongyun Wang, Zheng Jiao or Yihua Bei.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Associate Editor Nicola Smart oversaw the review of this article.

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 14845 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhu, Y., Chai, Y., Su, Z. et al. Danlou Tablet Protects Against Myocardial Infarction Through Promoting eNOS-Dependent Endothelial Protection and Angiogenesis. J. of Cardiovasc. Trans. Res. 17, 403–416 (2024). https://doi.org/10.1007/s12265-023-10437-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12265-023-10437-y

Keywords

Navigation