Skip to main content
SpringerLink
Log in

Axin2 depletion in macrophages alleviated senescence and increased immune response after myocardial infarction

  • Letter to the Editor
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective and design

This study aimed to investigate Axin2 effects on myocardial infarction (MI) using a macrophage Axin2 conditional knockout (cKO) mouse model, RAW264.7 cell line, and human subepicardial tissues from patients with coronary artery bypass graft (CABG).

Material or subjects

Axin2 cKO mice showed decreased cardiac function, reduced edema, increased lymphangiogenesis, and improved repair in MI Few studies border zones. Hypoxic macrophages with Axin2 depletion exhibited decreased senescence, elevated IL6 expression, and increased LYVE1 transcription. Senescent macrophages decreased in patients with CABG and low Axin2 expression.

Treatment

Treatment options included in this study were MI induction in Axin2 cKO mice, in vitro experiments with RAW264.7 cells, and analysis of human subepicardial tissues.

Methods

Assays included MI induction, in vitro experiments, and tissue analysis with statistical tests applied.

Results

Axin2 cKO improved cardiac function, reduced edema, enhanced lymphangiogenesis, and decreased senescence. Hypoxic macrophages with Axin2 depletion showed reduced senescence, increased IL6 expression, and elevated LYVE1 transcription. Senescent macrophages decreased in patients with CABG and low Axin2 expression.

Conclusion

Targeting Axin2 emerges as a novel therapeutic strategy for regulating cardiac lymphatics and mitigating cell senescence post-MI, evidenced by improved outcomes in Axin2-deficient conditions.

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

Data availability

Not applicable.

References

  1. Tsao CW, Aday AW, Almarzooq ZI, Alonso A, Beaton AZ, Bittencourt MS, et al. Heart disease and stroke statistics-2022 update: a report from the American heart association. Circulation. 2022;145(8):e153-639.

    Article  PubMed  Google Scholar 

  2. Chang J, Liu X, Sun Y. Mortality due to acutemyocardial infarction in China from 1987 to 2014: Secular trends and ageperiod-cohort effects. Int J Cardiol. 2017;227:229–38.

    Article  PubMed  Google Scholar 

  3. You J, Wang X, Wu J, Gao L, Wang X, Du P, et al. Predictors and prognosis of left ventricular thrombus in post-myocardial infarction patients with left ventricular dysfunction after percutaneous coronary intervention. J Thorac Dis. 2018;10:4912–22.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Lee JR, Park BW, Park JH, Lim S, Kwon SP, Hwang JW, et al. Local delivery of a senolytic drug in ischemia and reperfusion-injured heart attenuates cardiac remodeling and restores impaired cardiac function. Acta Biomater. 2021;135:520–33.

    Article  CAS  PubMed  Google Scholar 

  5. Zhang Z, Tian X, Lu JY, Boit K, Ablaeva J, Zakusilo FT, et al. Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice. Nature. 2023;621(7977):196–205.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  6. He J, Wo D, Ma E, Wang Q, Chen J, Gao Q, et al. Huoxin pill prevents excessive inflammation and cardiac dysfunction following myocardial infarction by inhibiting adverse Wnt/β-catenin signaling activation. Phytomedicine. 2022;104: 154293.

    Article  CAS  PubMed  Google Scholar 

  7. Meyer IS, Li X, Meyer C, Voloshanenko O, Pohl S, Boutros M, et al. Blockade of Wnt secretion attenuates myocardial ischemia-reperfusion injury by modulating the inflammatory response. Int J Mol Sci. 2022;23(20):12252.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Assmus B, Iwasaki M, Schächinger V, Roexe T, Koyanagi M, Iekushi K, et al. Acute myocardial infarction activates progenitor cells and increases Wnt signalling in the bone marrow. Eur Heart J. 2012;33(15):1911–9.

    Article  CAS  PubMed  Google Scholar 

  9. Gao E, Lei YH, Shang X, Huang ZM, Zuo L, Boucher M, et al. A novel and efficient model of coronary artery ligation and myocardial infarction in the mouse. Circ Res. 2010;107:1445–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Dutta P, Courties G, Wei Y, Leuschner F, Gorbatov R, Robbins CS, et al. Myocardial infarction accelerates atherosclerosis. Nature. 2012;487:325–9.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  11. Marino A, Zhang Y, Rubinelli L, Riemma MA, Ip JE, Di Lorenzo A. Pressure overload leads to coronary plaque formation, progression, and myocardial events in ApoE–/– mice. JCI Insight. 2019;4(9): e128220.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Horikoshi T, Obata JE, Nakamura T, Fujioka D, Watanabe Y, Nakamura K, et al. Persistent dysfunction of coronary endothelial vasomotor responses is related to atheroma plaque progression in the infarct-related coronary artery of AMI survivors. J Atheroscler Thromb. 2019;26(12):1062–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ruzza A, Czer LSC, Arabia F, Vespignani R, Esmailian F, Cheng W, et al. Left ventricular reconstruction for postinfarction left ventricular aneurysm: review of surgical techniques. Tex Heart Inst J. 2017;44:326–35.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Yan X, Zhang H, Fan Q, Hu J, Tao R, Chen Q, et al. Dectin-2 deficiency modulates Th1 differentiation and improves wound healing after myocardial infarction. Circ Res. 2017;120:1116–29.

    Article  CAS  PubMed  Google Scholar 

  15. Jackson BM, Gorman JH, Moainie SL, Guy TS, Narula N, Narula J, et al. Extension of borderzone myocardium in postinfarction dilated cardiomyopathy. J Am Col Cardiol. 2002;40:1160–7.

    Article  Google Scholar 

  16. Ratcliffe MB. Non-ischemic infarct extension: a new type of infarct enlargement and a potential therapeutic target. J Am Col Cardiol. 2002;40:1168–71.

    Article  Google Scholar 

  17. Zheng Y, Qi B, Gao W, Qi Z, Liu Y, Wang Y, et al. Macrophages-related genes biomarkers in the deterioration of atherosclerosis. Front Cardiovasc Med. 2022;9: 890321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zheng Y, Gao W, Zhang Q, Cheng X, Liu Y, Qi Z, et al. Ferroptosis and autophagy-related genes in the pathogenesis of ischemic cardiomyopathy. Front Cardiovasc Med. 2022;9: 906753.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zheng Y, Lang Y, Qi Z, Qi B, Gao W, Hu X, et al. Macrophage-related genes biomarkers in left ventricular remodeling induced by heart failure. Rev Cardiovasc Med. 2022;23(3):109.

    Article  PubMed  Google Scholar 

  20. Swirski FK, Nahrendorf M. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science. 2013;339:161–6.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hulsmans M, Clauss S, Xiao L, Aguirre AD, King KR, Hanley A, et al. Macrophages facilitate electrical conduction in the heart. Cell. 2017;169(3):510-522.e20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kieken F, Mutsaers N, Dolmatova E, Virgil K, Wit AL, Kellezi A, et al. Structural and molecular mechanisms of gap junction remodeling in epicardial border zone myocytes following myocardial infarction. Circ Res. 2009;104:1103–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yang Y, Huang T, Zhang H, Li X, Shi S, Tian X, et al. Formononetin improves cardiac function and depressive behaviours in myocardial infarction with depression by targeting GSK-3β to regulate macrophage/microglial polarization. Phytomedicine. 2023;109: 154602.

    Article  CAS  PubMed  Google Scholar 

  24. Yan Y, Tang D, Chen M, Huang J, Xie R, Jonason JH, et al. Axin2 controls bone remodeling through the beta-catenin-BMP signaling pathway in adult mice. J Cell Sci. 2009;122(Pt 19):3566–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mishra M, Muthuramu I, Kempen H, Geest BD. Administration of apo A-I (Milano) nanoparticles reverses pathological remodelling, cardiac dysfunction, and heart failure in a murine model of HFpEF associated with hypertension. Sci Rep. 2020;10(1):8382.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to express my gratitude to all those who helped us during the writing of this manuscript. They thank all the peer reviewers for their opinions and suggestions.

Funding

This work was sponsored by Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-035A), Tianjin biomedical industry chain innovation Project (21ZXSYSY00030), Tianjin Health Research Project (TJWJ2022XK026), Tianjin Health Research Project (TJWJ2022MS020), Tianjin “Project + Team” Key Training Special Project(XC202040), Tianjin “131” Innovative Talent Team Project (201939), Key Project of Tianjin Natural Science Foundation (21JCZDJC00240), the Tianjin Municipal Health and Health Committee Science and Technology Project (ZD20001), Tianjin Health Committee traditional Chinese medicine and integrated traditional Chinese and Western medicine project (2021139), Tianjin Science and Technology Project (21JCYBJC01250), the National Natural Science Foundation of China (82370420), Tianjin Health Research Project (TJWJ2023XK018, TJWJ2023QN046), and Tianjin Science and Technology Project (21JCYBJC01590).

Author information

Author notes

  1. $Yue Zheng, Yuchao Wang and Bingcai Qi contributed equally.

Authors and Affiliations

  1. School of Medicine, Nankai University, Tianjin, 300071, China

    Yue Zheng, Yuchao Wang, Wenqing Gao & Tong Li

  2. Department of Heart Center, The Third Central Hospital of Tianjin, 83 Jintang Road, Hedong District, Tianjin, 300170, China

    Yue Zheng, Yuchao Wang, Wenqing Gao & Tong Li

  3. Nankai University Affiliated Third Center Hospital, No. 83, Jintang Road, Hedong District, Tianjin, 300170, China

    Yue Zheng, Yuchao Wang, Wenqing Gao & Tong Li

  4. The Third Central Clinical College of Tianjin Medical University, Tianjin, 300170, China

    Bingcai Qi, Yanwu Liu & Tong Li

  5. Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin, China

    Yue Zheng, Yuchao Wang, Bingcai Qi, Wenqing Gao, Yanwu Liu & Tong Li

  6. Tianjin ECMO Treatment and Training Base, Tianjin, 300170, China

    Yue Zheng, Yuchao Wang, Bingcai Qi, Wenqing Gao, Yanwu Liu & Tong Li

  7. Artificial Cell Engineering Technology Research Center, Tianjin, China

    Yue Zheng, Yuchao Wang, Bingcai Qi, Wenqing Gao, Yanwu Liu & Tong Li

Authors
  1. Yue Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuchao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bingcai Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wenqing Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yanwu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YZ conceived the idea. YZ, BC Q, YC W, YW L, and QZ did animal results. YZ analyzed the data. YZ, QZ, and BC Q visualized the results. YZ wrote the manuscript. YZ, WQ G, and TL supervised the manuscript. All authors contributed to the article and approved the submitted version.

Corresponding author

Correspondence to Tong Li.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Ethical approval and consent to participate

This study was approved by the Ethics Committee of Nankai University (no. 2022-SYDWLL-000486).

Additional information

Responsible Editor: John Di Battista.

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.

11_2023_1843_MOESM1_ESM.tif

Supplementary file1 STAT3 knockdown validation in macrophages. (A–B) qPCR (A) and WB analysis (B) of STAT3 knockdown in RAW264.7 macrophages. ** P<0.01 (TIF 1263 KB)

11_2023_1843_MOESM2_ESM.tif

Supplementary file2 The severity of heart failure in mice model and human samples. (A) The NT-proBNP expressions were determined using ELISA in Axin2 cKO and control mice underwent MI or SHAM operation. (B) The NT-proBNP expressions were determined using ELISA in human epicardial samples between Axin2 high and low expression. ** P<0.01; *** P<0.001; ns, not significant (TIF 1818 KB)

Supplementary file3 (DOCX 19 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zheng, Y., Wang, Y., Qi, B. et al. Axin2 depletion in macrophages alleviated senescence and increased immune response after myocardial infarction. Inflamm. Res. 73, 407–414 (2024). https://doi.org/10.1007/s00011-023-01843-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-023-01843-8

Keywords

Search

Navigation