Skip to main content

Advertisement

SpringerLink
Log in

Agathis dammara Extract and its Monomer Araucarone Attenuate Abdominal Aortic Aneurysm in Mice

  • Original Article
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Background

Abdominal aortic aneurysm (AAA) is a chronic vascular disease wherein the inflammation of vascular smooth muscle cells (VSMCs) plays a pivotal role in its development. Effectively mitigating AAA involves inhibiting VSMC inflammation. Agathis dammara (Lamb.) Rich, recognized for its robust anti-inflammatory and antioxidant attributes, has been employed as a traditional medicinal resource. Nonetheless, there is a dearth of information regarding the potential of Agathis dammara extract (AD) in attenuating AAA, specifically by diminishing vascular inflammation, notably VSMC inflammation. Furthermore, the active constituents of AD necessitate identification.

Aim of the Study

This study sought to ascertain the efficacy of AD in reducing AAA, evaluate its impact on VSMC inflammation, and elucidate whether the monomer araucarone (AO) in AD acts as an active component against AAA.

Materials and Methods

The extraction of AD was conducted and subjected to analysis through High-Performance Liquid Chromatography (HPLC) and mass spectrometry. The isolation of the AO monomer followed, involving the determination of its content and purity. Subsequently, the effects of AD and AO on VSMC inflammation were assessed in vitro, encompassing an examination of inflammatory factors such as IL-6 and IL-18, as well as the activation of matrix metalloproteinase 9 (MMP9) in tumor necrosis factor-alpha (TNF-α)-stimulated VSMCs. To explore the inhibitory effects of AD/AO on AAA, C57BL/6J male mice were subjected to oral gavage (100 mg/kg) or intraperitoneal injection (50 mg/kg) of AD and AO in a porcine pancreatic elastase (PPE)-induced AAA model (14 days). This facilitated the observation of abdominal aorta dilatation, remodeling, elastic fiber disruption, and macrophage infiltration. Additionally, a three-day PPE mouse model was utilized to assess the effects of AD and AO (administered at 100 mg/kg via gavage) on acute inflammation and MMP9 expression in blood vessels. The mechanism by which AD/AO suppresses the inflammatory response was probed through the examination of NF-κB/NLRP3 pathway activation in VSMCs and aortas.

Results

Liquid Chromatography-Mass Spectrometry (LC–MS) revealed that AO constituted 15.36% of AD's content, with a purity of 96%. Subsequent pharmacological investigations of AO were conducted in parallel with AD. Both AD and AO exhibited the ability to inhibit TNF-α-induced VSMC inflammation and MMP production in vitro. Furthermore, both substances effectively prevented PPE-induced AAA in mice, whether administered through gavage or intraperitoneal injection, evidenced by decreased vascular diameter dilation, disruption of elastin fiber layers, and infiltration of inflammatory cells. In the three-day PPE mouse model, AD and AO mitigated the heightened expression of inflammatory factors and the elevated expression of MMP9 induced by PPE. The activation of the NF-κB/NLRP3 pathway in both VSMCs and aortas was significantly suppressed by treatment with AD or AO.

Conclusions

Through suppressing NF-κB/NLRP3 pathway activation, AD effectively mitigates the inflammatory response in VSMCs, mitigates inflammation in aortas, prevents extracellular matrix degradation, and consequently impedes the progression of AAA. AO emerges as one of the active compounds in AD responsible for inhibiting VSMC inflammation and inhibiting AAA development.

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
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Data Availability

When necessary, raw data is available on request.

Code Availability

Not applicable.

Abbreviations

AAA:

Abdominal aortic aneurysm

AD:

Agathis dammara Extract

AO:

Araucarone

ECM:

Extracellular matrix

IL-6/1β/18:

Interleukin 6/1β/18

MCP-1:

Monocyte chemoattractant protein-1

MMP:

Matrix metalloproteinase

MTT:

Methyl thiazolyl tetrazolium

NF-κB:

Nuclear factor kappa B

NLRP3:

NOD-like receptor thermal protein domain associated protein 3

PPE:

Porcine pancreatic elastase

TNF-α:

Tumor necrosis factor-α

VSMC:

Vascular smooth muscle cell

References

  1. Golledge J. Abdominal aortic aneurysm: update on pathogenesis and medical treatments. Nat Rev Cardiol. 2019;16(4):225–42. https://doi.org/10.1038/s41569-018-0114-9.

    Article  PubMed  Google Scholar 

  2. Sakalihasan N, Michel J-B, Katsargyris A, et al. Abdominal aortic aneurysms. Nat Rev Dis Primers. 2018;4(1):34. https://doi.org/10.1038/s41572-018-0030-7.

    Article  PubMed  Google Scholar 

  3. Wang YD, Liu ZJ, Ren J, Xiang MX. Pharmacological therapy of abdominal aortic aneurysm: an update. Curr Vasc Pharmacol. 2018;16(2):114–24. https://doi.org/10.2174/1570161115666170413145705.

    Article  PubMed  CAS  Google Scholar 

  4. Qian GQ, Adeyanju O, Olajuyin A, Guo X. Abdominal aortic aneurysm formation with a focus on vascular smooth muscle cells. Life-Basel. 2022;12(2):ARTN 191. https://doi.org/10.3390/life12020191.

    Article  CAS  Google Scholar 

  5. Sorokin V, Vickneson K, Kofidis T, et al. Role of vascular smooth muscle cell plasticity and interactions in vessel wall inflammation. Front Immunol. 2020;11:ARTN 599415. https://doi.org/10.3389/fimmu.2020.599415.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Petsophonsakul P, Furmanik M, Forsythe R, et al. Role of vascular smooth muscle cell phenotypic switching and calcification in aortic aneurysm formation involvement of vitamin K-dependent processes. Arterioscler Thromb Vasc Biol. 2019;39(7):1351–68. https://doi.org/10.1161/Atvbaha.119.312787.

    Article  PubMed  CAS  Google Scholar 

  7. Rombouts KB, Merrienboer TAR, Ket JCF, Bogunovic N, Velden J, Yeung KK. The role of vascular smooth muscle cells in the development of aortic aneurysms and dissections. Eur J Clin Invest. 2021;52(4):e13697. https://doi.org/10.1111/eci.13697.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Shi JY, Guo J, Li ZD, Xu BH, Miyata M. Importance of NLRP3 inflammasome in abdominal aortic aneurysms. J Atheroscler Thromb. 2021;28(5):454–66. https://doi.org/10.5551/jat.RV17048.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Zheng YD, Xu L, Dong NG, Li F. NLRP3 inflammasome: the rising star in cardiovascular diseases. Front Cardiovasc Med. 2022;9:927061. https://doi.org/10.3389/fcvm.2022.927061.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Wortmann M, Peters AS, Erhart P, Korfer D, Bockler D, Dihlmann S. Inflammasomes in the pathophysiology of aortic disease. Cells. 2021;10(9):ARTN 2433. https://doi.org/10.3390/cells10092433.

    Article  CAS  Google Scholar 

  11. Ren XS, Tong Y, Ling L, et al. NLRP3 gene deletion attenuates angiotensin II-induced phenotypic transformation of vascular smooth muscle cells and vascular remodeling. Cell Physiol Biochem. 2017;44(6):2269–80. https://doi.org/10.1159/000486061.

    Article  PubMed  CAS  Google Scholar 

  12. Ren PP, Wu D, Appel R, et al. Targeting the NLRP3 inflammasome with inhibitor MCC950 prevents aortic aneurysms and dissections in mice. J Am Heart Assoc. 2020;9(7):e014044. https://doi.org/10.1161/JAHA.119.014044.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Wang AY, Yue SS, Peng AK, Qi R. A review of research progress on agathis dammara and its application prospects for cardiovascular diseases and fatty liver disease. Mini-Rev Med Chem. 2021;21(6):670–6. https://doi.org/10.2174/1389557520666201117110834.

    Article  PubMed  CAS  Google Scholar 

  14. Khan AW, ul Abidin Z, Sahibzada MUK, et al. Potential biomedical applications of Araucaria araucana as an antispasmodic, bronchodilator, vasodilator, and antiemetic: involvement of calcium channels. J Ethnopharmacol. 2022;298:115651. https://doi.org/10.1016/j.jep.2022.115651.

    Article  PubMed  CAS  Google Scholar 

  15. Frezza C, Venditti A, De Vita D, et al. Phytochemistry, chemotaxonomy, and biological activities of the araucariaceae family-a review. Plants-Basel. 2020;9(7):ARTN 888. https://doi.org/10.3390/plants9070888.

    Article  Google Scholar 

  16. Enzell CR, Thomas BR. The wood resin of agathis australis salis. - Structure and stereochemistry of the main constituents. Tetrahedron Lett. 1964;5(8):391–7. https://doi.org/10.1016/0040-4039(64)83003-3.

    Article  Google Scholar 

  17. Wang YX, Chen C, Wang QY, Cao YN, Xu L, Qi R. Inhibitory effects of cycloastragenol on abdominal aortic aneurysm and its related mechanisms. Br J Pharmacol. 2019;176(2):282–96. https://doi.org/10.1111/bph.14515.

    Article  PubMed  CAS  Google Scholar 

  18. Chen C, Wang Y, Cao Y, et al. Mechanisms underlying the inhibitory effects of probucol on elastase-induced abdominal aortic aneurysm in mice. Br J Pharmacol. 2019;177(1):204–16. https://doi.org/10.1111/bph.14857.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Chhabra A, Rani V. Gel-based gelatin zymography to examine matrix metalloproteinase activity in cell culture. Methods Mol Biol. 2018;1731:83–96. https://doi.org/10.1007/978-1-4939-7595-2_9.

    Article  PubMed  CAS  Google Scholar 

  20. Lal AR, Cambie RC, Rutledge PS, Woodgate PD. Chemistry of Fijian plants. 6. Ent-pimarane and ent-abietane diterpenes from Euphorbia-Fidjiana. Phytochemistry. 1990;29(7):2239–46. https://doi.org/10.1016/0031-9422(90)83045-3.

    Article  CAS  Google Scholar 

  21. Kuivaniemi H, Ryer EJ, Elmore JR, Tromp G. Understanding the pathogenesis of abdominal aortic aneurysms. Expert Rev Cardiovasc Ther. 2015;13(9):975–87. https://doi.org/10.1586/14779072.2015.1074861.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Bossone E, Eagle KA. Epidemiology and management of aortic disease: aortic aneurysms and acute aortic syndromes. Nat Rev Cardiol. 2020;18(5):331–48. https://doi.org/10.1038/s41569-020-00472-6.

    Article  PubMed  Google Scholar 

  23. Yuan Z, Lu Y, Wei J, Wu J, Yang J, Cai Z. Abdominal aortic aneurysm: roles of inflammatory cells. Front Immunol. 2021;11: 609161. https://doi.org/10.3389/fimmu.2020.609161.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Maguire EM, Pearce SWA, Xiao R, Oo AY, Xiao QZ. Matrix metalloproteinase in abdominal aortic aneurysm and aortic dissection. Pharmaceuticals. 2019;12(3):ARTN 118. https://doi.org/10.3390/ph12030118.

    Article  Google Scholar 

  25. Yu J, Liu R, Huang JH, Wang LX, Wang W. Inhibition of Phosphatidylinositol 3-kinease suppresses formation and progression of experimental abdominal aortic aneurysms. Sci Rep. 2017;7(1):15208. https://doi.org/10.1038/s41598-017-15207-w.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Li D, Guo Y-y, Cen X-f, et al. Lupeol protects against cardiac hypertrophy via TLR4-PI3K-Akt-NF-κB pathways. Acta Pharmacol Sin. 2021;43(8):1989–2002. https://doi.org/10.1038/s41401-021-00820-3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Zhu Q, Enkhjargal B, Huang L, et al. Aggf1 attenuates neuroinflammation and BBB disruption via PI3K/Akt/NF-κB pathway after subarachnoid hemorrhage in rats. J Neuroinflammation. 2018;15(1):178. https://doi.org/10.1186/s12974-018-1211-8.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Fu H, Shen Q-r, Zhao Y, et al. Activating α7nAChR ameliorates abdominal aortic aneurysm through inhibiting pyroptosis mediated by NLRP3 inflammasome. Acta Pharmacol Sin. 2022;43(10):2585–95. https://doi.org/10.1038/s41401-022-00876-9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Wu D, Ren PP, Zheng YQ, et al. NLRP3 (Nucleotide oligomerization domain-like receptor family, pyrin domain containing 3)-caspase-1 inflammasome degrades contractile proteins: implications for aortic biomechanical dysfunction and aneurysm and dissection formation. Arterioscler Thromb Vasc Biol. 2017;37(4):694–706. https://doi.org/10.1161/Atvbaha.116.307648.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Coll RC, Robertson AAB, Chae JJ, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015;21(3):248-+. https://doi.org/10.1038/nm.3806.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

We would like to express our gratitude to the Home for Researchers (www.home-for-researchers.com) for their significant contribution to the generation of the graphical abstract.The graphical abstract is drawn by Figdraw (www.figdraw.com).

The image material of C56BL/6J mice used in this paper was obtained from ScienceSlides 2016.

Funding

This work was supported by the National Key Research and Development Program (No. 2019YFE0113500).

Author information

Authors and Affiliations

  1. Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100191, China

    Qingyi Zhang, Chang Di & Rong Qi

  2. State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China

    Qingyi Zhang, Chang Di & Rong Qi

  3. NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing, China

    Qingyi Zhang, Chang Di & Rong Qi

  4. Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing, China

    Qingyi Zhang, Chang Di & Rong Qi

  5. State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China

    Qingyi Zhang, Chang Di & Rong Qi

  6. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China

    Zeyu Cai

  7. Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China

    Zhewei Yu & Yingkun Qiu

Authors
  1. Qingyi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zeyu Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhewei Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chang Di
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yingkun Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rong Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Qingyi Zhang: designed and performed experiments and wrote up the manuscript. Zhewei Yu: prepared AD extraction, purified and characterized AO monomer. Zeyu Cai: designed experiments and revised manuscript. Chang Di: experiments’ assistant and manuscript revision. Yingkun Qiu: conceived and designed the preparation, purification and characterization of AD and AO. Rong Qi: conceived and designed the study and revised manuscript.

Corresponding authors

Correspondence to Yingkun Qiu or Rong Qi.

Ethics declarations

Ethics Approval

All animal experiments in this study were approved by both the Biomedical Ethics Committee of Peking University and the Animal Experiment Advisory Committee of the Peking University Health Science Center (Ethics number LA2021045).

Consent to Participate

This research does not involve human experiments.

Consent for Publication

All authors agree to publish this article in Cardiovascular Drugs and Therapy.

Conflict of Interest

The authors declare no competing interests.

Additional information

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 559 KB)

Supplementary file2 (PDF 774 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

Zhang, Q., Cai, Z., Yu, Z. et al. Agathis dammara Extract and its Monomer Araucarone Attenuate Abdominal Aortic Aneurysm in Mice. Cardiovasc Drugs Ther (2023). https://doi.org/10.1007/s10557-023-07518-0

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10557-023-07518-0

Keywords

Search

Navigation