Skip to main content
SpringerLink
Log in

Aerobic exercise mitigates high-fat diet-induced cardiac dysfunction, pyroptosis, and inflammation by inhibiting STING-NLRP3 signaling pathway

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Obesity has been identified as an independent risk factor for cardiovascular disease. Recent reports have highlighted the significance of stimulator of interferon genes (STING)-NOD-like receptor protein 3 (NLRP3) signaling pathway mediated pyroptosis, and inflammation in cardiovascular disease. Previous studies have demonstrated that exercise training effectively prevents cardiac pyroptosis and inflammation in high-fat diet (HFD)-fed mice. However, it is currently unknown whether exercise reduces pyroptosis and inflammation in obese hearts by targeting the STING-NLRP3 signaling pathway. We investigated the impact of an 8-week aerobic exercise regimen on cardiac function, pyroptosis, inflammation, and the STING-NLRP3 signaling pathway in HFD-induced obese mice. Additionally, to explore the underlying mechanism of STING in exercise-mediated cardioprotection, we administered intraperitoneal injections of the STING agonist diABZI to the mice. Furthermore, to investigate the role of the STING-NLRP3 signaling pathway in HFD-induced cardiac dysfunction, we administered adeno-associated virus 9 (AAV9) encoding shRNA targeting STING (shRNA-STING) via tail vein injection to knockdown STING expression specifically in mouse hearts. After one week of AAV9 injection, we intraperitoneally injected nigericin as an NLRP3 agonist. We first found that aerobic exercise effectively suppressed HFD-mediated upregulation of STING and NLRP3 in the hearts. Moreover, we demonstrated that the protective effect of aerobic exercise in HFD-induced cardiac dysfunction, pyroptosis, and inflammation was impaired by stimulating the STING pathway using diABZI. Additionally, activation of the NLRP3 with nigericin abolished the ameliorative effect of STING deficiency in HFD-induced cardiac dysfunction, pyroptosis, and inflammation. Based on these findings, we concluded that 8-week aerobic exercise alleviates HFD-induced cardiac dysfunction, pyroptosis, and inflammation by targeting STING-NLRP3 signaling pathway. Inhibition of STING-NLRP3 signaling pathway may serve as a promising therapeutic strategy against obesity-induced cardiomyopathy.

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

Similar content being viewed by others

Data availability

The datasets used and analyzed during the current study are available upon request by contacting with the corresponding author.

Abbreviations

HFD:

High-fat diet

STING:

Stimulator of interferon genes

NLRP3:

NOD-like receptor protein 3

AE:

Aerobic exercise

ASC:

Apoptosis-associated speck-like protein

GSDMD:

Gasdermin D

IL-1β:

Interleukin-1β

ND:

Normal diet

AAV9:

Adeno-associated virus 9

LVIDd:

Left ventricle internal dimension diastole

LVIDs:

Left ventricle internal dimension systole

EF:

Ejection fraction

FS:

Fractional shortening

References

  1. Powell-Wiley TM, Poirier P, Burke LE et al (2021) Obesity and cardiovascular disease: a scientific statement from the american heart association. Circulation 143(21):E984–E1010

    Article  PubMed  PubMed Central  Google Scholar 

  2. Xu ZJ, Qin Y, Lv BB et al (2022) Intermittent fasting improves high-fat diet-induced obesity cardiomyopathy via alleviating lipid deposition and apoptosis and decreasing m6a methylation in the heart. Nutrients 14(2):251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zhu MY, Peng LL, Huo SQ et al (2023) STAT3 signaling promotes cardiac injury by upregulating NCOA4-mediated ferritinophagy and ferroptosis in high-fat-diet fed mice. Free Radical Biol Med 201:111–125

    Article  CAS  Google Scholar 

  4. Hu QX, Zhang HL, Cortés NG et al (2020) Increased Drp1 acetylation by lipid overload induces cardiomyocyte death and heart dysfunction. Circ Res 126(4):456–470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chen XD, Li HY, Wang KW et al (2019) Aerobic exercise ameliorates myocardial inflammation, fibrosis and apoptosis in high-fat-diet rats by inhibiting P2X7 purinergic receptors. Front Physiol 10:1286

    Article  PubMed  PubMed Central  Google Scholar 

  6. Kim K, Ahn N, Jung S (2018) Comparison of endoplasmic reticulum stress and mitochondrial biogenesis responses after 12 weeks of treadmill running and ladder climbing exercises in the cardiac muscle of middle-aged obese rats. Braz J Med Biol Res 51(10):e7508

    Article  PubMed  PubMed Central  Google Scholar 

  7. Ko JB, Jang YC, Quindry J et al (2023) Exercise-induced antisenescence and autophagy restoration mitigate metabolic disorder-induced cardiac disruption in mice. Med Sci Sports Exerc 55(3):376–388

    Article  CAS  PubMed  Google Scholar 

  8. Alexandre-Santos B, Alves R, Matsuura C et al (2020) Modulation of cardiac renin-angiotensin system, redox status and inflammatory profile by different volumes of aerobic exercise training in obese rats. Free Radical Biol Med 156:125–136

    Article  CAS  Google Scholar 

  9. Sokolova M, Sjaastad I, Louwe MC et al (2019) NLRP3 inflammasome promotes myocardial remodeling during diet-induced obesity. Front Immunol 10:1621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yue QX, Liu Y, Ji J et al (2023) Down-regulation of OIP5-AS1 inhibits obesity-induced myocardial pyroptosis and miR-22/NLRP3 inflammasome axis. Immun Inflamm Dis 11(10):e1066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Toldo S, Mezzaroma E, Buckley LF et al (2022) Targeting the NLRP3 inflammasome in cardiovascular diseases. Pharmacol Ther 236:108053

    Article  CAS  PubMed  Google Scholar 

  12. Mangan MSJ, Olhava EJ, Roush WR et al (2018) Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discovery 17(9):688

    Article  CAS  PubMed  Google Scholar 

  13. Toldo S, Abbate A (2023) The role of the NLRP3 inflammasome and pyroptosis in cardiovascular diseases. Nat Rev Cardiol. https://doi.org/10.1038/s41569-023-00946-3

    Article  PubMed  Google Scholar 

  14. Oduro PK, Zheng XX, Wei JN et al (2022) The cGAS-STING signaling in cardiovascular and metabolic diseases: Future novel target option for pharmacotherapy. Acta Pharmaceutica Sinica B 12(1):50–75

    Article  CAS  PubMed  Google Scholar 

  15. Xiao Y, Zhao C, Tai Y et al (2023) STING mediates hepatocyte pyroptosis in liver fibrosis by epigenetically activating the NLRP3 inflammasome. Redox Biol 62:102691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kar S, Shahshahan HR, Hackfort BT et al (2019) Exercise training promotes cardiac hydrogen sulfide biosynthesis and mitigates pyroptosis to prevent high-fat diet-induced diabetic cardiomyopathy. Antioxidants 8(12):638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kesherwani V, Chavali V, Hackfort BT et al (2015) Exercise ameliorates high fat diet induced cardiac dysfunction by increasing interleukin 10. Front Physiol 6:124

    Article  PubMed  PubMed Central  Google Scholar 

  18. Xu ZJ, Qin Y, Lv BB et al (2022) Effects of moderate-intensity continuous training and high-intensity interval training on testicular oxidative stress, apoptosis and m6A Methylation in obese male mice. Antioxidants 11(10):1874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fang GY, Li XC, Yang FY et al (2023) Amentoflavone mitigates doxorubicin-induced cardiotoxicity by suppressing cardiomyocyte pyroptosis and inflammation through inhibition of the STING/NLRP3 signalling pathway. Phytomedicine 117:154922

    Article  CAS  PubMed  Google Scholar 

  20. Li N, Zhou H, Wu HM et al (2019) STING-IRF3 contributes to lipopolysaccharide-induced cardiac dysfunction, inflammation, apoptosis and pyroptosis by activating NLRP3. Redox Biol 24:101215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yan ML, Li Y, Luo QM et al (2022) Mitochondrial damage and activation of the cytosolic DNA sensor cGAS-STING pathway lead to cardiac pyroptosis and hypertrophy in diabetic cardiomyopathy mice. Cell Death Discov 8(1):258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gaidt MM, Ebert TS, Chauhan D et al (2017) The DNA inflammasome in human myeloid cells is initiated by a STING-cell death program upstream of NLRP3. Cell 171(5):1110–1124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gastaldi S, Rocca C, Gianquinto E et al (2023) Discovery of a novel 1,3,4-oxadiazol-2-one-based NLRP3 inhibitor as a pharmacological agent to mitigate cardiac and metabolic complications in an experimental model of diet-induced metaflammation. Eur J Med Chem 257:115542

    Article  CAS  PubMed  Google Scholar 

  24. Jiang JZ, Ni LY, Zhang XX et al (2023) Moderate-intensity exercise maintains redox homeostasis for cardiovascular health. Adv Biol 7(4):e2200204

    Article  Google Scholar 

  25. Chen HH, Chen C, Spanos M et al (2022) Exercise training maintains cardiovascular health: signaling pathways involved and potential therapeutics. Signal Transduct Target Ther 7(1):306

    Article  PubMed  PubMed Central  Google Scholar 

  26. Wong ND, Karthikeyan H, Fan WJ (2023) US population eligibility and estimated impact of semaglutide treatment on obesity prevalence and cardiovascular disease events. Cardiovasc Drugs Ther. https://doi.org/10.1007/s10557-023-07488-3

    Article  PubMed  Google Scholar 

  27. Swift DL, Johannsen NM, Lavie CJ et al (2014) The role of exercise and physical activity in weight loss and maintenance. Prog Cardiovasc Dis 56(4):441–447

    Article  PubMed  Google Scholar 

  28. Vega RB, Konhilas JP, Kelly DP et al (2017) Molecular mechanisms underlying cardiac adaptation to exercise. Cell Metab 25(5):1012–1026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Schrauwen-Hinderling VB, Hesselink MKC, Meex R et al (2010) Improved ejection fraction after exercise training in obesity is accompanied by reduced cardiac lipid content. J Clin Endocrinol Metab 95(4):1932–1938

    Article  CAS  PubMed  Google Scholar 

  30. Li SC, Qian XL, Gong JH et al (2021) Exercise training reverses lipotoxicity-induced cardiomyopathy by inhibiting HMGCS2. Med Sci Sports Exerc 53(1):47–57

    Article  CAS  PubMed  Google Scholar 

  31. Gutiérrez-Cuevas J, Sandoval-Rodriguez A, Meza-Rios A et al (2021) Molecular mechanisms of obesity-linked cardiac dysfunction: an up-date on current knowledge. Cells 10(3):629

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ren J, Wu NN, Wang SY et al (2021) Obesity cardiomyopathy: evidence, mechanisms, and therapeutic implications. Physiol Rev 101(4):1745–1807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Scott L, Fender AC, Saljic A et al (2021) NLRP3 inflammasome is a key driver of obesity-induced atrial arrhythmias. Cardiovasc Res 117(7):1746–1759

    Article  CAS  PubMed  Google Scholar 

  34. Hopfner KP, Hornung V (2020) Molecular mechanisms and cellular functions of cGAS-STING signalling. Nat Rev Mol Cell Biol 21(9):501–521

    Article  CAS  PubMed  Google Scholar 

  35. Decout A, Katz JD, Venkatraman S et al (2021) The cGAS-STING pathway as a therapeutic target in inflammatory diseases. Nat Rev Immunol 21(9):548–569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Luo W, Zou XY, Wang YD et al (2023) Critical role of the cGAS-STING pathway in doxorubicin-induced cardiotoxicity. Circ Res 132(11):E223–E242

    Article  CAS  PubMed  Google Scholar 

  37. Ma XM, Geng K, Law BYK et al (2023) Lipotoxicity-induced mtDNA release promotes diabetic cardiomyopathy by activating the cGAS-STING pathway in obesity-related diabetes. Cell Biol Toxicol 39(1):277–299

    Article  CAS  PubMed  Google Scholar 

  38. Chen J, Zhu T, Yu DY et al (2023) Moderate intensity of treadmill exercise rescues TBI-induced ferroptosis, neurodegeneration, and cognitive impairments via suppressing STING pathway. Mol Neurobiol 60(9):4872–4896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fu JN, Wu H (2023) Structural mechanisms of NLRP3 inflammasome assembly and activation. Annu Rev Immunol 41:301–316

    Article  CAS  PubMed  Google Scholar 

  40. Pan M, Tai RQ, Liu YR et al (2022) Pyroptosis: a possible link between obesity-related inflammation and inflammatory diseases. J Cell Physiol 237(2):1245–1265

    Article  Google Scholar 

  41. Vandanmagsar B, Youm YH, Ravussin A et al (2011) The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 17(2):179–188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Luo BB, Li B, Wang WK et al (2014) NLRP3 gene silencing ameliorates diabetic cardiomyopathy in a type 2 diabetes rat model. PLoS ONE 9(8):e104771

    Article  ADS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work is particularly supported by Taiyuan University of Technology high-level talent scientific research funding.

Funding

This study was supported by Science and Technology Service Project of Winter Sports Management Center of General Administration of Sport of China (No. 20212001045) and Taiyuan University of Technology high-level talent scientific research funding.

Author information

Authors and Affiliations

  1. College of Physical Education, Taiyuan University of Technology, Taiyuan Shanxi, 030024, China

    Zujie Xu, Zheying Ma & Xiaoqin Zhao

  2. Division of Sports Science and Physical Education, Tsinghua University, Beijing, 100084, China

    Bing Zhang

Authors
  1. Zujie Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zheying Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaoqin Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ZX and BZ researched and designed the experiment. ZX and ZM performed the experiment and analyzed the data. ZX, XZ, and BZ contributed reagents and materials. ZX wrote and edited the manuscript. All authors have read and critically revised the manuscript and approved the final version.

Corresponding author

Correspondence to Zujie Xu.

Ethics declarations

Competing interests

The authors declare that they have no competing interests.

Ethics approval and consent to participate

All animal experiments were approved by the Institutional Animal Care and Use Committee of Taiyuan University of Technology and Tsinghua University.

Consent for publication

No human studies or human tissues were used in this research study.

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.

11010_2024_4950_MOESM1_ESM.docx

Supplementary file1 (DOCX 27 KB)—Table S1 Aerobic exercise protocol. Table S2 Biometric and echocardiographic measurements in experimental mice. Table S3 Primer sequences used for Real-Time qPCR.

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

Xu, Z., Ma, Z., Zhao, X. et al. Aerobic exercise mitigates high-fat diet-induced cardiac dysfunction, pyroptosis, and inflammation by inhibiting STING-NLRP3 signaling pathway. Mol Cell Biochem (2024). https://doi.org/10.1007/s11010-024-04950-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11010-024-04950-0

Keywords

Search

Navigation