Arterial Occlusive Disease | Elucidating the mechanisms of formononetin in modulating atherosclerotic plaque formation in ApoE-/- mice | springermedicine.com

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BMC Cardiovascular Disorders

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Open Access 01-12-2024 | Arterial Occlusive Disease | Research

Elucidating the mechanisms of formononetin in modulating atherosclerotic plaque formation in ApoE-/- mice

Authors: Ying He, Youde Cai, Dingling Wei, Liping Cao, Qiansong He, Yazhou Zhang

Published in: BMC Cardiovascular Disorders | Issue 1/2024

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Abstract

Background

Atherosclerosis(AS) poses a pressing challenge in contemporary medicine. Formononetin (FMN) plays a crucial role in its prevention and treatment. However, the detailed impact of FMN on the stability of atherosclerotic plaques and its underlying mechanisms remain to be elucidated.

Methods

An intervention consisting of FMN was given along with a high-fat food regimen in the ApoE-/- mouse model. The investigation included the evaluation of the degree of atherosclerotic lesion, the main components of the plaque, lipid profiles, particular markers indicating M1/M2 macrophage phenotypes, the quantities of factors related to inflammation, the infiltration of macrophages, and the identification of markers linked to the α7nAChR/JAK2/STAT3 axis effect molecules.

Results

The evaluation of aortic morphology in ApoE-/-mice revealed that FMN significantly improved the plaque area, fibrous cap protrusion, lipid deposition, and structural alterations on the aortic surface, among other markers of atherosclerosis,and there is concentration dependence. Furthermore, the lipid content of mouse serum was assessed, and the results showed that the low-, medium-, and high-dosage FMN groups had significantly lower levels of LDL-C, ox-LDL, TC, and TG. The results of immunohistochemical staining indicated that the low-, medium-, and high-dose FMN therapy groups had enhanced CD206 expression and decreased expression of CD68 and iNOS. According to RT-qPCR data, FMN intervention has the potential to suppress the expression of iNOS, COX-2, miR-155-5p, IL-6, and IL-1β mRNA, while promoting the expression of IL-10, SHIP1, and Arg-1 mRNA levels. However, the degree of inhibition varied among dosage groups. Western blot investigation of JAK/STAT signaling pathway proteins and cholinergic α7nAChR protein showed that p-JAK2 and p-STAT3 protein expression was suppressed at all dosages, whereas α7nAChR protein expression was enhanced.

Conclusions

According to the aforementioned findings, FMN can reduce inflammation and atherosclerosis by influencing macrophage polarization, blocking the JAK/STAT signaling pathway, and increasing α7nAChR expression.

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1.

Sanz J, Fayad ZA. Imaging of atherosclerotic cardiovascular disease. Nature. 2008;451:953–7. https://doi.org/10.1038/nature06803.ADSCrossRefPubMed

2.

Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, Barengo NC, Beaton AZ, Benjamin EJ, Benziger CP, Bonny A. Global Burden of Cardiovascular Diseases and Risk Factors, 1990–2019: Update From the GBD 2019 Study. J Am Coll Cardiol. 2020;76:2982–3021. https://doi.org/10.1016/j.jacc.2020.11.010.CrossRefPubMedPubMedCentral

3.

Hetherington I, Totary-Jain H. Anti-atherosclerotic therapies: milestones, challenges, and emerging innovations. Mol Ther. 2022;30:3106–17. https://doi.org/10.1016/j.ymthe.2022.08.024.CrossRefPubMedPubMedCentral

4.

Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell. 2011;145:341–55. https://doi.org/10.1016/j.cell.2011.04.005.CrossRefPubMedPubMedCentral

5.

Colin S, Chinetti-Gbaguidi G, Staels B. Macrophage phenotypes in atherosclerosis. ImmunolRev. 2014;262:153–66. https://doi.org/10.1111/imr.12218.CrossRef

6.

Leitinger N, Schulman IG. Phenotypic polarization of macrophages in atherosclerosis. Arterioscler Thromb Vasc Biol. 2013;33:1120–6. https://doi.org/10.1161/ATVBAHA.112.300173.CrossRefPubMedPubMedCentral

7.

Moore KJ, Sheedy FJ, Fisher EA. Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol. 2013;13:709–21. https://doi.org/10.1038/nri3520.CrossRefPubMedPubMedCentral

8.

Italiani P, Boraschi D. From monocytes to M1/M2 macrophages: phenotypical vs. functional differentiation. Front Immunol. 2014;5:514. https://doi.org/10.3389/fimmu.2014.00514.CrossRefPubMedPubMedCentral

9.

Chen Q, Lv J, Yang W, Xu B, Wang Z, Yu Z, Wu J, Yang Y, Han Y. Targeted inhibition of STAT3 as a potential treatment strategy for atherosclerosis. Theranostics. 2019;9:6424. https://doi.org/10.7150/thno.35528.CrossRefPubMedPubMedCentral

10.

Liao M, Xu J, Clair AJ, Ehrman B, Graham LM, Eagleton MJ. Local and systemic alterations in signal transducers and activators of transcription (STAT) associated with human abdominal aortic aneurysms. J Surg Res. 2012;176:321–8. https://doi.org/10.1016/j.jss.2011.05.041.CrossRefPubMed

11.

Mo ZC, Xiao J, Liu XH, Hu YW, Li XX, Yi GH, Wang Z, Tang YL, Liao DF, Tang CK. AOPPs inhibits cholesterol efflux by downregulating ABCA1 expression in a JAK/STAT signaling pathway-dependent manner. J Atheroscler Thromb. 2011;18:796–807. https://doi.org/10.5551/jat.6569.CrossRefPubMed

12.

Hajiasgharzadeh K, Somi MH, Sadigh-Eteghad S, Mokhtarzadeh A, Shanehbandi D, Mansoori B, Mohammadi A, Doustvandi MA, Baradaran B. The dual role of alpha7 nicotinic acetylcholine receptor in inflammation-associated gastrointestinal cancers. Heliyon. 2020,6(3). https://doi.org/10.1016/j.heliyon.2020.e03611

13.

Johansson ME, Ulleryd MA, Bernardi A, Lundberg AM, Andersson A, Folkersen L, Fogelstrand L, Islander U, Yan ZQ, Hansson GK. α7 Nicotinic acetylcholine receptor is expressed in human atherosclerosis and inhibits disease in mice—Brief report. Arterioscler Thromb Vasc Biol. 2014;34:2632–6. https://doi.org/10.1161/ATVBAHA.114.303892.CrossRefPubMed

14.

Kooijman S, Meurs I, Van der Stoep M, Habets KL, Lammers B, Berbée JF, Havekes LM, van Eck M, Romijn JA, Korporaal SJ, Rensen PC. Hematopoietic α7 nicotinic acetylcholine receptor deficiency increases inflammation and platelet activation status, but does not aggravate atherosclerosis. J Thromb Hemost. 2015;13:126–35. https://doi.org/10.1111/jth.12765.CrossRef

15.

Ting-Ting LI, Zhi-Bin WA, Yang LI, Feng CA, Bing-You YA, Kuang HX. The mechanisms of traditional Chinese medicine underlying the prevention and treatment of atherosclerosis. Chin J Nat Med. 2019;17:401–12. https://doi.org/10.1016/S1875-5364(19)30048-2.ADSCrossRef

16.

Zhi W, Liu Y, Wang X, Zhang H. Recent advances of traditional Chinese medicine for the prevention and treatment of atherosclerosis. J Ethnopharmacol. 2023;301:115749. https://doi.org/10.1016/j.jep.2022.115749.CrossRefPubMed

17.

Tay KC, Tan LT, Chan CK, Hong SL, Chan KG, Yap WH, Pusparajah P, Lee LH, Goh BH. Formononetin: A Review of Its Anticancer Potentials and Mechanisms. Front Pharmacol. 2019;10:820. https://doi.org/10.3389/fphar.2019.00820.CrossRefPubMedPubMedCentral

18.

Ma C, Xia R, Yang S, Liu L, Zhang J, Feng K, Shang Y, Qu J, Li L, Chen N, Xu S. Formononetin attenuates atherosclerosis by regulating interaction between KLF4 and SRA in apoE-/- mice. Theranostics. 2020;10:090–1106. https://doi.org/10.17150/thno.38115.CrossRef

19.

Zhang B, Hao Z, Zhou W, Zhang S, Sun M, Li H, Hou N, Jing C, Zhao M. Formononetin protects against ox-LDL-induced endothelial dysfunction by activating PPAR-γ signaling based on network pharmacology and experimental validation. Bioengineered. 2021;12:4887–98. https://doi.org/10.1080/21655979.2021.1959493.CrossRefPubMedPubMedCentral

20.

Arbab-Zadeh A, Fuster V. From detecting the vulnerable plaque to managing the vulnerable patient: JACC state-of-the-art review. J Am Coll Cardiol. 2019;74:1582–93. https://doi.org/10.1016/j.jacc.2019.07.062.CrossRefPubMed

21.

Ho MM, Manughian-Peter A, Spivia WR, Taylor A, Fraser DA. Macrophage molecular signaling and inflammatory responses during ingestion of atherogenic lipoproteins are modulated by complement protein C1q. Atherosclerosis. 2016;253:38–46. https://doi.org/10.1016/j.atherosclerosis.2016.08.019.CrossRefPubMedPubMedCentral

22.

Kishore SP, Blank E, Heller DJ, Patel A, Peters A, Price M, Vidula M, Fuster V, Onuma O, Huffman MD, Vedanthan R. Modernizing the World Health Organization list of essential medicines for preventing and controlling cardiovascular diseases. J Am Coll Cardiol. 2018;71:564–74. https://doi.org/10.1016/j.jacc.2017.11.056.CrossRefPubMed

23.

Yang S, Yuan HQ, Hao YM, Ren Z, Qu SL, Liu LS, Wei DH, Tang ZH, Zhang JF, Jiang ZS. Macrophage polarization in atherosclerosis. Clin Chim Acta. 2020;501:142–6. https://doi.org/10.1016/j.cca.2019.10.034.CrossRefPubMed

24.

Yunna C, Mengru H, Lei W, Weidong C. Macrophage M1/M2 polarization. Eur J Pharmacol. 2020;877:173090. https://doi.org/10.1016/j.ejphar.2020.173090.CrossRefPubMed

25.

Luo Y, Lu S, Gao Y, Yang K, Wu D, Xu X, Sun G, Sun X, Araloside C. Araloside C attenuates atherosclerosis by modulating macrophage polarization via Sirt1-mediated autophagy. Aging. 2020;12:1704–24. https://doi.org/10.18632/aging.102708.CrossRefPubMedPubMedCentral

26.

Luo P, Wang Y, Zhao C, Guo J, Shi W, Ma H, Liu T, Yan D, Huo S, Wang M, Li C. Bazedoxifene exhibits anti-inflammation and anti-atherosclerotic effects via inhibition of IL-6/IL-6R/STAT3 signaling. Eur J Pharmacol. 2021;893: 173822. https://doi.org/10.1016/j.ejphar.2020.173822.CrossRefPubMed

27.

Yu Z, Zheng X, Wang C, Chen C, Ning N, Peng D, Liu T, Pan W. The Traditional Chinese Medicine Hua Tuo Zai Zao Wan Alleviates Atherosclerosis by Deactivation of Inflammatory Macrophages. Evid Based Complement Alternat Med. 2022;2200662. doi:https://doi.org/10.1155/2022/2200662

28.

Wang J, Cai E, An X, Wang J. Ginaton reduces M1-polarized macrophages in hypertensive cardiac remodeling via NF-κB signaling. Front Pharmacol. 2023;14:1104871. https://doi.org/10.3389/fphar.2023.1104871.CrossRefPubMedPubMedCentral

29.

Miyoshi T, Li Y, Shih DM, Wang X, Laubach VE, Matsumoto AH, Helm GA, Lusis AJ, Shi W. Deficiency of inducible NO synthase reduces advanced but not early atherosclerosis in apolipoprotein E-deficient mice. Life Sci. 2006;79:525–31. https://doi.org/10.1016/j.lfs.2006.01.043.CrossRefPubMed

30.

Huang H, Koelle P, Fendler M, Schröttle A, Czihal M, Hoffmann U, Conrad M, Kuhlencordt PJ. Induction of inducible nitric oxide synthase (iNOS) expression by oxLDL inhibits macrophage derived foam cell migration. Atherosclerosis. 2014;235:213–22. https://doi.org/10.1016/j.atherosclerosis.2014.04.020.CrossRefPubMed

31.

Liao H, Li Y, Zhai X, Zheng B, Banbury L, Zhao X, Li R. Comparison of inhibitory effects of safflower decoction and safflower injection on protein and mRNA expressions of iNOS and IL-1β in LPS-activated RAW264. 7 cells. J Immunol Res. 2019. https://doi.org/10.1155/2019/1018274

32.

Xu S, Ni HE, Chen HW, Dai QY. The role of STAT3 in atherosclerosis. New Medicine. 2020;30:383–8. https://doi.org/10.12173/j.issn.1004-5511.2020.05.07.CrossRef

33.

Krueger JG, McInnes IB, Blauvelt A. Tyrosine kinase 2 and Janus kinase-signal transducer and activator of transcription signaling and inhibition in plaque psoriasis. J Am Acad Dermatol. 2022;86:148–57. https://doi.org/10.1016/j.jaad.2021.06.869.CrossRefPubMed

34.

Xu L, Zhang H, Wang Y, Yang A, Dong X, Gu L, Liu D, Ding N, Jiang Y. FABP4 activates the JAK2/STAT2 pathway via Rap1a in the homocysteine-induced macrophage inflammatory response in ApoE-/- mice atherosclerosis. Lab Invest. 2020;102:25–37. https://doi.org/10.1038/s41374-021-00679-2.CrossRef

35.

Tang Y, Liu W, Wang W, Fidler T, Woods B, Levine RL, Tall AR, Wang N. Inhibition of JAK2 Suppresses Myelopoiesis and Atherosclerosis in Apoe-/- Mice. Cardiovasc Drugs Ther. 2020;34:145–52. https://doi.org/10.1007/s10557-020-06943-9.CrossRefPubMedPubMedCentral

36.

Yang X, Jia J, Yu Z, Duanmu Z, He H, Chen S, Qu C. Inhibition of JAK2/STAT3/SOCS3 signaling attenuates atherosclerosis in rabbit. BMC Cardiovasc Disord. 2020;20:133. https://doi.org/10.1186/s12872-020-01391-7.CrossRefPubMedPubMedCentral

37.

Vieira-Alves I, Coimbra-Campos L, Sancho M, Da Silva RF, Cortes SF, Lemos VS. Role of the α7 Nicotinic Acetylcholine Receptor in the Pathophysiology of Atherosclerosis. Front Physiol. 2020;11:621769. https://doi.org/10.3389/fphys.2020.621769.CrossRefPubMedPubMedCentral

38.

Ulleryd MA, Mjörnstedt F, Panagaki D, Yang LJ, Engevall K, Gutiérrez S, Wang Y, Gan LM, Nilsson H, Michaëlsson E, Johansson ME. Stimulation of alpha 7 nicotinic acetylcholine receptor (α7nAChR) inhibits atherosclerosis via immunomodulatory effects on myeloid cells. Atherosclerosis. 2019;287:122–33. https://doi.org/10.1016/j.atherosclerosis.2019.06.903.CrossRefPubMed

39.

Wang D, Ren Y, Sun W, Gong J, Zou X, Dong H, Xu L, Wang K, Lu F. Berberine Ameliorates Glucose Metabolism in Diabetic Rats through the alpha7 Nicotinic Acetylcholine Receptor-Related Cholinergic Anti-Inflammatory Pathway. Planta Med. 2022;88:33–42. https://doi.org/10.1055/a-1385-8015.CrossRefPubMed

40.

Zou LF, Liu DF, Yang H, Zhou CH, Deng SB, Xu NS, He XM, Liu YQ, Shao M, Yu LZ, Liu JS. Salvianolic acids from Salvia miltiorrhiza Bunge and their anti-inflammatory effects through the activation of α7nAchR signaling. J Ethnopharmacol. 2023;116743. https://doi.org/10.1016/j.jep.2023.116743

Title: Elucidating the mechanisms of formononetin in modulating atherosclerotic plaque formation in ApoE-/- mice
Authors: Ying He
Youde Cai
Dingling Wei
Liping Cao
Qiansong He
Yazhou Zhang
Publication date: 01-12-2024
Publisher: BioMed Central
Keyword: Arterial Occlusive Disease
Published in: BMC Cardiovascular Disorders / Issue 1/2024
Electronic ISSN: 1471-2261
DOI: https://doi.org/10.1186/s12872-024-03774-6

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