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Isofraxidin Alleviates Myocardial Infarction Through NLRP3 Inflammasome Inhibition

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Abstract

Isofraxidin is a well-known coumarin compound refined from traditional Chinese medicines. It has been previously demonstrated to play an anti-inflammatory role in various inflammatory conditions. However, the effect of isofraxidin on myocardial infarction (MI) remains uncovered. In this study, we aimed to investigate the effect of isofraxidin on MI. MI mice was created and triphenyltetrazolium chloride (TTC) staining as well as echocardiographic evaluation were conducted to analyze the severity of MI. Oxygen-glucose deprivation (OGD) was used for the mimics of ischemic stress in murine cardiomyocytes, and Cell Counting Kit-8 (CCK-8), Annexin V, and lactate dehydrogenase (LDH) release assays were conducted for cell viability. Western blot was used for the detection of NOD-like receptor family, pyrin domain containing 3 (NLRP3), and adapter protein apoptosis-associated speck-like protein (ASC) in heart tissues and cardiomyocytes. Real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) were applied for the detection of proinflammatory cytokines. We found that isofraxidin alleviated the severity of MI and produced a cardio-protective effect against OGD damage. Isofraxidin also decreased the overall and local inflammatory reaction in MI. Those effects were through the inhibition of the NLRP3 inflammasome. Taken together, we initially reported the cardio-protective and alleviative effect of isofraxidin on MI and uncovered its underlying mechanism related to the NLRP3 inflammasome inhibition.

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References

  1. Raber, I., C.P. McCarthy, M. Vaduganathan, D.L. Bhatt, D.A. Wood, J.G.F. Cleland, R.S. Blumenthal, and J.W. McEvoy. 2019. The rise and fall of aspirin in the primary prevention of cardiovascular disease. Lancet 393 (10186): 2155–2167. https://doi.org/10.1016/S0140-6736(19)30541-0.

    Article  PubMed  Google Scholar 

  2. Oder, D., M.S. Topp, and P. Nordbeck. 2019. Coronary B-cell lymphoma infiltration causing myocardial infarction. European Heart Journal. https://doi.org/10.1093/eurheartj/ehz538.

  3. Koechlin, L., J. Boeddinghaus, T. Nestelberger, D. Wussler, J. Walter, F.J. Martin-Sanchez, N. Geigy, et al. 2019. Early diagnosis of myocardial infarction in patients with a history of coronary artery bypass grafting. Journal of the American College of Cardiology 74 (4): 587–589. https://doi.org/10.1016/j.jacc.2019.05.044.

    Article  PubMed  Google Scholar 

  4. Lu, L., M. Liu, R. Sun, Y. Zheng, and P. Zhang. 2015. Myocardial infarction: Symptoms and treatments. Cell Biochemistry and Biophysics 72 (3): 865–867. https://doi.org/10.1007/s12013-015-0553-4.

    Article  CAS  PubMed  Google Scholar 

  5. Kim, C.Y., J.H. Lee, S.Y. Jang, M.H. Bae, D.H. Yang, H.S. Park, Y. Cho, et al. 2019. Usefulness of calculation of cardiovascular risk factors to predict outcomes in patients with acute myocardial infarction. The American Journal of Cardiology. https://doi.org/10.1016/j.amjcard.2019.06.010.

  6. Siri, S.R.A., B.M. Eliassen, B.K. Jacobsen, M. Melhus, A.R. Broderstad, V.L. Michalsen, and T. Braaten. 2019. Changes in conventional cardiovascular risk factors and the estimated 10-year risk of acute myocardial infarction or cerebral stroke in Sami and non-Sami populations in two population-based cross-sectional surveys: The SAMINOR study. BMJ Open 9 (7): e028939. https://doi.org/10.1136/bmjopen-2019-028939.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Sigirci, S., S.S. Yildiz, K. Keskin, G. Cetinkal, G. Aksan, A. Gurdal, S. Cetin, H. Kilci, and K.O. Kilickesmez. 2019. The predictive value of stress hyperglycemia on thrombus burden in nondiabetic patients with ST-segment elevation myocardial infarction. Blood Coagulation & Fibrinolysis. https://doi.org/10.1097/MBC.0000000000000832.

  8. Rauf, A., M. Shah, D.M. Yellon, and S.M. Davidson. 2019. The role of caspase 1 in ischemia/reperfusion injury of the myocardium. Journal of Cardiovascular Pharmacology. https://doi.org/10.1097/FJC.0000000000000694.

  9. Ibanez, B., A.H. Aletras, A.E. Arai, H. Arheden, J. Bax, C. Berry, C. Bucciarelli-Ducci, et al. 2019. Cardiac MRI endpoints in myocardial infarction experimental and clinical trials: JACC scientific expert panel. Journal of the American College of Cardiology 74 (2): 238–256. https://doi.org/10.1016/j.jacc.2019.05.024.

    Article  PubMed  Google Scholar 

  10. Hu, J., C.X. Huang, P.P. Rao, G.Q. Cao, Y. Zhang, J.P. Zhou, L.Y. Zhu, M.X. Liu, and G.G. Zhang. 2019. MicroRNA-155 inhibition attenuates endoplasmic reticulum stress-induced cardiomyocyte apoptosis following myocardial infarction via reducing macrophage inflammation. European Journal of Pharmacology 857: 172449. https://doi.org/10.1016/j.ejphar.2019.172449.

    Article  CAS  PubMed  Google Scholar 

  11. Felger, J.C. 2018. Imaging the role of inflammation in mood and anxiety-related disorders. Current Neuropharmacology 16 (5): 533–558. https://doi.org/10.2174/1570159X15666171123201142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ablasser, A., and Z.J. Chen. 2019. cGAS in action: Expanding roles in immunity and inflammation. Science 363 (6431). https://doi.org/10.1126/science.aat8657.

  13. Gong, T., W. Jiang, and R. Zhou. 2018. Control of inflammasome activation by phosphorylation. Trends in Biochemical Sciences 43 (9): 685–699. https://doi.org/10.1016/j.tibs.2018.06.008.

    Article  CAS  PubMed  Google Scholar 

  14. Shin, J.I., K.H. Lee, Y.H. Joo, J.M. Lee, J. Jeon, H.J. Jung, M. Shin, et al. 2019. Inflammasomes and autoimmune and rheumatic diseases: A comprehensive review. J Autoimmun: 102299. https://doi.org/10.1016/j.jaut.2019.06.010.

  15. Winsor, N., C. Krustev, J. Bruce, D.J. Philpott, and S.E. Girardin. 2019. Canonical and noncanonical inflammasomes in intestinal epithelial cells. Cell Microbiol: e13079. https://doi.org/10.1111/cmi.13079.

  16. Henderson, J., S. Bhattacharyya, J. Varga, and S. O’Reilly. 2018. Targeting TLRs and the inflammasome in systemic sclerosis. Pharmacology & Therapeutics 192: 163–169. https://doi.org/10.1016/j.pharmthera.2018.08.003.

    Article  CAS  Google Scholar 

  17. An, N., Y. Gao, Z. Si, H. Zhang, L. Wang, C. Tian, M. Yuan, et al. 2019. Regulatory mechanisms of the NLRP3 inflammasome, a novel immune-inflammatory marker in cardiovascular diseases. Frontiers in Immunology 10: 1592. https://doi.org/10.3389/fimmu.2019.01592.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kelley, N., D. Jeltema, Y. Duan, and Y. He. 2019. The NLRP3 inflammasome: An overview of mechanisms of activation and regulation. International Journal of Molecular Sciences 20 (13). https://doi.org/10.3390/ijms20133328.

  19. Shao, B.Z., Z.Q. Xu, B.Z. Han, D.F. Su, and C. Liu. 2015. NLRP3 inflammasome and its inhibitors: A review. Frontiers in Pharmacology 6: 262. https://doi.org/10.3389/fphar.2015.00262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Toldo, S., and A. Abbate. 2018. The NLRP3 inflammasome in acute myocardial infarction. Nature Reviews. Cardiology 15 (4): 203–214. https://doi.org/10.1038/nrcardio.2017.161.

    Article  CAS  PubMed  Google Scholar 

  21. Gao, R., H. Shi, S. Chang, Y. Gao, X. Li, C. Lv, H. Yang, H. Xiang, J. Yang, L. Xu, and Y. Tang. 2019. The selective NLRP3-inflammasome inhibitor MCC950 reduces myocardial fibrosis and improves cardiac remodeling in a mouse model of myocardial infarction. International Immunopharmacology 74: 105575. https://doi.org/10.1016/j.intimp.2019.04.022.

    Article  CAS  PubMed  Google Scholar 

  22. Bian, Y., X. Li, P. Pang, X.L. Hu, S.T. Yu, Y.N. Liu, X. Li, N. Wang, J.H. Wang, W. Xiao, W.J. du, and B.F. Yang. 2019. Kanglexin, a novel anthraquinone compound, protects against myocardial ischemic injury in mice by suppressing NLRP3 and pyroptosis. Acta Pharmacologica Sinica: 1–8. https://doi.org/10.1038/s41401-019-0307-8.

  23. Yamazaki, T., and T. Tokiwa. 2010. Isofraxidin, a coumarin component from Acanthopanax senticosus, inhibits matrix metalloproteinase-7 expression and cell invasion of human hepatoma cells. Biological & Pharmaceutical Bulletin 33 (10): 1716–1722. https://doi.org/10.1248/bpb.33.1716.

    Article  CAS  Google Scholar 

  24. Su, X., B. Liu, F. Gong, J. Yin, Q. Sun, Y. Gao, Z. Lv, and X. Wang. 2019. Isofraxidin attenuates IL-1beta-induced inflammatory response in human nucleus pulposus cells. Journal of Cellular Biochemistry 120 (8): 13302–13309. https://doi.org/10.1002/jcb.28604.

    Article  CAS  PubMed  Google Scholar 

  25. Li, J., X. Li, Z. Li, L. Zhang, Y. Liu, H. Ding, and S. Yin. 2017. Isofraxidin, a coumarin component improves high-fat diet induced hepatic lipid homeostasis disorder and macrophage inflammation in mice. Food & Function 8 (8): 2886–2896. https://doi.org/10.1039/c7fo00290d.

    Article  CAS  Google Scholar 

  26. Lin, J., X. Li, W. Qi, Y. Yan, K. Chen, X. Xue, X. Xu, Z. Feng, and X. Pan. 2018. Isofraxidin inhibits interleukin-1beta induced inflammatory response in human osteoarthritis chondrocytes. International Immunopharmacology 64: 238–245. https://doi.org/10.1016/j.intimp.2018.09.003.

    Article  CAS  PubMed  Google Scholar 

  27. Liu, L., Q. Mu, W. Li, W. Xing, H. Zhang, T. Fan, H. Yao, and L. He. 2015. Isofraxidin protects mice from LPS challenge by inhibiting pro-inflammatory cytokines and alleviating histopathological changes. Immunobiology 220 (3): 406–413. https://doi.org/10.1016/j.imbio.2014.10.007.

    Article  CAS  PubMed  Google Scholar 

  28. Liao, Q., S. Qu, L.X. Tang, L.P. Li, D.F. He, C.Y. Zeng, and W.E. Wang. 2019. Irisin exerts a therapeutic effect against myocardial infarction via promoting angiogenesis. Acta Pharmacologica Sinica 40: 1314–1321. https://doi.org/10.1038/s41401-019-0230-z.

    Article  CAS  PubMed  Google Scholar 

  29. Yu, W., G. Jin, J. Zhang, and W. Wei. 2019. Selective activation of cannabinoid receptor 2 attenuates myocardial infarction via suppressing NLRP3 inflammasome. Inflammation 42 (3): 904–914. https://doi.org/10.1007/s10753-018-0945-x.

    Article  CAS  PubMed  Google Scholar 

  30. Niu, X., W. Xing, W. Li, T. Fan, H. Hu, and Y. Li. 2012. Isofraxidin exhibited anti-inflammatory effects in vivo and inhibited TNF-alpha production in LPS-induced mouse peritoneal macrophages in vitro via the MAPK pathway. International Immunopharmacology 14 (2): 164–171. https://doi.org/10.1016/j.intimp.2012.06.022.

    Article  CAS  PubMed  Google Scholar 

  31. Niu, X., Y. Wang, W. Li, Q. Mu, H. Li, H. Yao, and H. Zhang. 2015. Protective effects of isofraxidin against lipopolysaccharide-induced acute lung injury in mice. International Immunopharmacology 24 (2): 432–439. https://doi.org/10.1016/j.intimp.2014.12.041.

    Article  CAS  PubMed  Google Scholar 

  32. Takahashi, M. 2019. Role of NLRP3 inflammasome in cardiac inflammation and remodeling after myocardial infarction. Biological & Pharmaceutical Bulletin 42 (4): 518–523. https://doi.org/10.1248/bpb.b18-00369.

    Article  CAS  Google Scholar 

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Funding

This work was supported by a Zhejiang Provincial Medicine Health Science and Technology Program (No. 2018ZB057).

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Authors and Affiliations

  1. Department of Cardiology, The Affiliated Hospital of Hangzhou Normal University, 126 Wenzhou Road, Hangzhou, Zhejiang, China

    Guofan Chen

  2. Department of Cardiology, Shengli Oilfield Central Hospital, 31 Jinan Road, Dongying, Shandong, China

    Xiaozheng Song

  3. Department of Cardiology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, 318 Chaowang Road, Hangzhou, Zhejiang, China

    Dongming Lin

  4. Department of Cardiology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, 261 Huansha Road, Hangzhou, Zhejiang, China

    Peng Xu

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Correspondence to Peng Xu.

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Supplemental Fig. 1

. Isofraxidin increased the levels of proinflammatory cytokines in MI mice models and cardiomyocytes under the challenge of OGD. (a,b) The left anterior descending coronary artery was occluded for the creation of MI mice models. Mice with mere thoracotomy were treated as the sham group. Isofraxidin at the dose of 20 mg/kg body weight was intraperitoneally given to mice at 5 min before occlusion. Saline in the equal volume was intraperitoneally injected as vehicle. Quantitative analysis of IL-4 and IL-10 in serum at 6 h after occlusion (n=6 per group). **P<0.01 vs. sham group; ##P<0.01 vs. MI+Vehicle group; data are presented as mean±SEM. (c,d) Primary cardiomyocytes were harvested from mice and challenged with OGD for 4 h. Isofraxidin at the dose of 100 μM was treated at 10 min before suffering OGD. PBS in the equal volume was given as vehicle. Quantitative analysis of supernatant IL-4 and IL-10 (n=6 per group). **P<0.01 vs. normal group; ##P<0.01 vs. OGD+Vehicle group; data are presented as mean±SEM. (PNG 247 kb)

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Chen, G., Song, X., Lin, D. et al. Isofraxidin Alleviates Myocardial Infarction Through NLRP3 Inflammasome Inhibition. Inflammation 43, 712–721 (2020). https://doi.org/10.1007/s10753-019-01158-z

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