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Potential therapeutic strategies for myocardial infarction: the role of Toll-like receptors

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Abstract

Myocardial infarction (MI) is a life-threatening condition among patients with cardiovascular diseases. MI increases the risk of stroke and heart failure and is a leading cause of morbidity and mortality worldwide. Several genetic and epigenetic factors contribute to the development of MI, suggesting that further understanding of the pathomechanism of MI might help in the early management and treatment of this disease. Toll-like receptors (TLRs) are well-known members of the pattern recognition receptor (PRR) family and contribute to both adaptive and innate immunity. Collectively, studies suggest that TLRs have a cardioprotective effect. However, prolonged TLR activation in the response to signals generated by damage-associated molecular patterns (DAMPs) results in the release of inflammatory cytokines and contributes to the development and exacerbation of myocardial inflammation, MI, ischemia–reperfusion injury, myocarditis, and heart failure. The objective of this review is to discuss and summarize the association of TLRs with MI, highlighting their therapeutic potential for the development of advanced TLR-targeted therapies for MI.

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References

  1. Mendis S, Thygesen K, Kuulasmaa K, Giampaoli S, Mähönen M, Ngu Blackett K, Lisheng L. Writing group on behalf of the participating experts of the WHO consultation for revision of WHO definition of myocardial infarction. World Health Organization Definition of Myocardial Infarction: 2008–09 Revision. Int J Epidemiol. 2011;40(1):139–46. https://doi.org/10.1093/ije/dyq165.

    Article  PubMed  Google Scholar 

  2. Havranek EP, Mujahid MS, Barr DA, Blair IV, Cohen MS, Cruz-Flores S, Davey-Smith G, Dennison-Himmelfarb CR, Lauer MS, Lockwood DW, Rosal M, Yancy CW. Social determinants of risk and outcomes for cardiovascular disease. Circulation. 2015;132(9):873–98. https://doi.org/10.1161/CIR.0000000000000228.

    Article  PubMed  Google Scholar 

  3. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, De Ferranti SD, Floyd J, Fornage M, Gillespie C. Heart disease and stroke statistics—2017 update: a report from the American Heart Association. Circulation. 2017;135(10):e146–603.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Nakatani D, Sakata Y, Suna S, Usami M, Matsumoto S, Shimizu M, Sumitsuji S, Kawano S, Ueda Y, Hamasaki T. Incidence, predictors, and subsequent mortality risk of recurrent myocardial infarction in patients following discharge for acute myocardial infarction. Circ J 2012, CJ-11.

  5. Kim HO, Kim JM, Woo JS, Beom Park C, Man Cho J, Lee SU, Kim CJ, Jeong MH, Kim W, KAMIR Investigators. Circadian distribution of acute myocardial infarction in different age groups. Am J Cardiol. 2018;121(11):1279–84.

    Article  PubMed  Google Scholar 

  6. Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, Himmelfarb CD, Khera A, Lloyd-Jones D, McEvoy JW. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;74(10):e177–232.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Gianfagna F, Cugino D, Santimone I, Iacoviello L. From candidate gene to genome-wide association studies in cardiovascular disease. Thromb Res. 2012;129(3):320–4.

    Article  CAS  PubMed  Google Scholar 

  8. Yamada Y, Kato K, Oguri M, Horibe H, Fujimaki T, Yasukochi Y, Takeuchi I, Sakuma J. Identification of 13 novel susceptibility loci for early-onset myocardial infarction, hypertension, or chronic kidney disease. Int J Mol Med. 2018;42(5):2415–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Bagai A, Dangas GD, Stone GW, Granger CB. Reperfusion strategies in acute coronary syndromes. Circ Res. 2014;114(12):1918–28.

    Article  CAS  PubMed  Google Scholar 

  10. Bougouin W, Marijon E, Puymirat E, Defaye P, Celermajer DS, Le Heuzey J-Y, Boveda S, Kacet S, Mabo P, Barnay C. Incidence of sudden cardiac death after ventricular fibrillation complicating acute myocardial infarction: a 5-year cause-of-death analysis of the FAST-MI 2005 registry. Eur Heart J. 2014;35(2):116–22.

    Article  PubMed  Google Scholar 

  11. Wu, X.; Iroegbu, C. D.; Peng, J.; Guo, J.; Yang, J.; Fan, C. Cell death and exosomes regulation after myocardial infarction and ischemia-reperfusion. Front Cell Dev Biol. 2021, 9. https://doi.org/10.3389/fcell.2021.673677.

  12. Bu D, Su Z, Zou J, Meng M, Wang C. Study of the mechanism underlying therapeutic effect of compound longmaining on myocardial infarction using a network pharmacology-based approach. Biomed Pharmacother. 2019;118: 109234.

    Article  CAS  PubMed  Google Scholar 

  13. Lemaitre B, Nicolas E, Michaut L, Reichhart J-M, Hoffmann JA. The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell. 1996;86(6):973–83.

    Article  CAS  PubMed  Google Scholar 

  14. Roh JS, Sohn DH. Damage-associated molecular patterns in inflammatory diseases. Immune Network 2018;18 (4).

  15. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on toll-like receptors. Nat Immunol. 2010;11(5):373–84.

    Article  CAS  PubMed  Google Scholar 

  16. Li M, Carpio DF, Zheng Y, Bruzzo P, Singh V, Ouaaz F, Medzhitov RM, Beg AA. An essential role of the NF-ΚB/Toll-like receptor pathway in induction of inflammatory and tissue-repair gene expression by necrotic cells. J Immunol. 2001;166(12):7128–35.

    Article  CAS  PubMed  Google Scholar 

  17. Viglianti GA, Lau CM, Hanley TM, Miko BA, Shlomchik MJ, Marshak-Rothstein A. Activation of autoreactive B cells by CpG DsDNA. Immunity. 2003;19(6):837–47.

    Article  CAS  PubMed  Google Scholar 

  18. Lau CM, Broughton C, Tabor AS, Akira S, Flavell RA, Mamula MJ, Christensen SR, Shlomchik MJ, Viglianti GA, Rifkin IR. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J Exp Med. 2005;202(9):1171–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cavassani KA, Ishii M, Wen H, Schaller MA, Lincoln PM, Lukacs NW, Hogaboam CM, Kunkel SL. TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events. J Exp Med. 2008;205(11):2609–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sioud M. Innate sensing of self and non-self RNAs by Toll-like receptors. Trends Mol Med. 2006;12(4):167–76.

    Article  CAS  PubMed  Google Scholar 

  21. Vabulas RM, Ahmad-Nejad P, da Costa C, Miethke T, Kirschning CJ, Häcker H, Wagner H. Endocytosed HSP60s Use Toll-like receptor 2 (TLR2) and TLR4 to activate the Toll/interleukin-1 receptor signaling pathway in innate immune cells. J Biol Chem. 2001;276(33):31332–9.

    Article  CAS  PubMed  Google Scholar 

  22. Vabulas RM, Ahmad-Nejad P, Ghose S, Kirschning CJ, Issels RD, Wagner H. HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J Biol Chem. 2002;277(17):15107–12.

    Article  CAS  PubMed  Google Scholar 

  23. Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, Mignot G, Maiuri MC, Ullrich E, Saulnier P. Toll-like receptor 4–dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 2007;13(9):1050–9.

    Article  CAS  PubMed  Google Scholar 

  24. Tian J, Avalos AM, Mao S-Y, Chen B, Senthil K, Wu H, Parroche P, Drabic S, Golenbock D, Sirois C. Toll-like receptor 9–dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol. 2007;8(5):487–96.

    Article  CAS  PubMed  Google Scholar 

  25. Zhang P, Cox CJ, Alvarez KM, Cunningham MW. Cutting edge: cardiac myosin activates innate immune responses through TLRs. J Immunol. 2009;183(1):27–31.

    Article  CAS  PubMed  Google Scholar 

  26. Okamura Y, Watari M, Jerud ES, Young DW, Ishizaka ST, Rose J, Chow JC, Strauss JF. The extra domain A of fibronectin activates Toll-like receptor 4. J Biol Chem. 2001;276(13):10229–33.

    Article  CAS  PubMed  Google Scholar 

  27. Tesar BM, Jiang D, Liang J, Palmer SM, Noble PW, Goldstein DR. The role of hyaluronan degradation products as innate alloimmune agonists. Am J Transplant. 2006;6(11):2622–35.

    Article  CAS  PubMed  Google Scholar 

  28. Jiang D, Liang J, Fan J, Yu S, Chen S, Luo Y, Prestwich GD, Mascarenhas MM, Garg HG, Quinn DA. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med. 2005;11(11):1173–9.

    Article  CAS  PubMed  Google Scholar 

  29. Schaefer L, Babelova A, Kiss E, Hausser H-J, Baliova M, Krzyzankova M, Marsche G, Young MF, Mihalik D, Götte M. The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages. J Clin Investig. 2005;115(8):2223–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Smiley ST, King JA, Hancock WW. Fibrinogen stimulates macrophage chemokine secretion through Toll-like receptor 4. J Immunol. 2001;167(5):2887–94.

    Article  CAS  PubMed  Google Scholar 

  31. Johnson GB, Brunn GJ, Kodaira Y, Platt JL. Receptor-mediated monitoring of tissue well-being via detection of soluble heparan sulfate by Toll-like receptor 4. J Immunol. 2002;168(10):5233–9.

    Article  CAS  PubMed  Google Scholar 

  32. Yu L, Wang L, Chen S. Endogenous Toll-like receptor ligands and their biological significance. J Cell Mol Med. 2010;14(11):2592–603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kawai T, Takeuchi O, Fujita T, Inoue J, Mühlradt PF, Sato S, Hoshino K, Akira S. Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J Immunol. 2001;167(10):5887–94.

    Article  CAS  PubMed  Google Scholar 

  34. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H, Bauer S. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science. 2004;303(5663):1526–9.

    Article  CAS  PubMed  Google Scholar 

  35. Hayashi F, Smith KD, Ozinsky A, Hawn TR, Eugene CY, Goodlett DR, Eng JK, Akira S, Underhill DM, Aderem A. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature. 2001;410(6832):1099–103.

    Article  CAS  PubMed  Google Scholar 

  36. Shishido T, Nozaki N, Yamaguchi S, Shibata Y, Nitobe J, Miyamoto T, Takahashi H, Arimoto T, Maeda K, Yamakawa M. Toll-like receptor-2 modulates ventricular remodeling after myocardial infarction. Circulation. 2003;108(23):2905–10.

    Article  CAS  PubMed  Google Scholar 

  37. Frantz S, Kelly RA, Bourcier T. Role of TLR-2 in the activation of nuclear factor ΚB by oxidative stress in cardiac myocytes. J Biol Chem. 2001;276(7):5197–203.

    Article  CAS  PubMed  Google Scholar 

  38. Wang L, Li Y-L, Zhang C-C, Cui W, Wang X, Xia Y, Du J, Li H-H. Inhibition of Toll-like receptor 2 reduces cardiac fibrosis by attenuating macrophage-mediated inflammation. Cardiovasc Res. 2014;101(3):383–92.

    Article  CAS  PubMed  Google Scholar 

  39. Wu RN, Yu TY, Zhou JC, Li M, Gao HK, Zhao C, Dong RQ, Peng D, Hu ZW, Zhang XW, Wu YQ. Targeting HMGB1 ameliorates cardiac fibrosis through restoring TLR2-mediated autophagy suppression in myocardial fibroblasts. Int J Cardiol. 2018;267:156–62. https://doi.org/10.1016/j.ijcard.2018.04.103.

    Article  PubMed  Google Scholar 

  40. Wang JW, Fontes MS, Wang X, Chong SY, Kessler EL, Zhang YN, D Haan JJ, Arslan F, De Jager SC, Timmers L, Van Veen TA. Leukocytic toll like receptor 2 deficiency preserves cardiac function and reduces fibrosis in sustained pressure overload. Sci Rep. 2017;7(1):1. https://doi.org/10.1038/s41598017-09451-3.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Arslan F, Smeets MB, O’Neill LA, Keogh B, McGuirk P, Timmers L, Tersteeg C, Hoefer IE, Doevendans PA, Pasterkamp G, de Kleijn DP. Myocardial ischemia/reperfusion injury is mediated by leukocytic toll-like receptor-2 and reduced by systemic administration of a novel anti–toll-like receptor-2 antibody. Circulation. 2010;121(1):80–90. https://doi.org/10.1161/CIRCULATIONAHA.109.880187.

    Article  CAS  PubMed  Google Scholar 

  42. Selejan S, Pöss J, Walter F, Hohl M, Kaiser R, Kazakov A, Böhm M, Link A. Ischaemia-induced up-regulation of Toll-like receptor 2 in circulating monocytes in cardiogenic shock. Eur Heart J. 2012;33(9):1085–94.

    Article  CAS  PubMed  Google Scholar 

  43. Ueland T, Espevik T, Kjekshus J, Gullestad L, Omland T, Squire IB, Frøland SS, Mollnes TE, Dickstein K, Aukrust P. Mannose binding lectin and soluble Toll-like receptor 2 in heart failure following acute myocardial infarction. J Cardiac Fail. 2006;12(8):659–63. https://doi.org/10.1016/j.cardfail.2006.07.002.

    Article  CAS  Google Scholar 

  44. Ha T, Hu Y, Liu L, Lu C, McMullen JR, Kelley J, Kao RL, Williams DL, Gao X, Li C. TLR2 ligands induce cardioprotection against ischaemia/reperfusion injury through a PI3K/Akt-dependent mechanism. Cardiovasc Res. 2010;87(4):694–703. https://doi.org/10.1093/cvr/cvq116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kumar S, Sunagar R, Gosselin E. Bacterial protein Toll-like-receptor agonists: a novel perspective on vaccine adjuvants. Front Immunol. 2019;10:1144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Boyd JH, Mathur S, Wang Y, Bateman RM, Walley KR. Toll-like receptor stimulation in cardiomyoctes decreases contractility and initiates an NF-ΚB dependent inflammatory response. Cardiovasc Res. 2006;72(3):384–93.

    Article  CAS  PubMed  Google Scholar 

  47. Arslan F, Smeets MB, O’Neill LA, Keogh B, McGuirk P, Timmers L, Tersteeg C, Hoefer IE, Doevendans PA, Pasterkamp G. Myocardial ischemia/reperfusion injury is mediated by leukocytic Toll-like receptor-2 and reduced by systemic administration of a novel anti–Toll-like receptor-2 antibody. Circulation. 2010;121(1):80–90.

    Article  CAS  PubMed  Google Scholar 

  48. Mersmann J, Berkels R, Zacharowski P, Tran N, Koch A, Iekushi K, Dimmeler S, Granja TF, Boehm O, Claycomb WC. Preconditioning by Toll-like receptor 2 agonist Pam3CSK4 reduces CXCL1-dependent leukocyte recruitment in murine myocardial ischemia/reperfusion injury. Crit Care Med. 2010;38(3):903–9.

    Article  CAS  PubMed  Google Scholar 

  49. Dong J-W, Vallejo JG, Tzeng H-P, Thomas JA, Mann DL. Innate immunity mediates myocardial preconditioning through Toll-like receptor 2 and TIRAP-dependent signaling pathways. Am J Physiol Heart Circ Physiol. 2010;298(3):H1079–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wang X, Ha T, Liu L, Hu Y, Kao R, Kalbfleisch J, Williams D, Li C. TLR3 mediates repair and regeneration of damaged neonatal heart through glycolysis dependent YAP1 regulated MiR-152 expression. Cell Death Differ. 2018;25(5):966–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chen C, Feng Y, Zou L, Wang L, Chen HH, Cai J-Y, Xu J-M, Sosnovik DE, Chao W. Role of extracellular RNA and TLR 3-Trif signaling in myocardial ischemia–reperfusion injury. J Am Heart Assoc. 2014;3(1): e000683.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Gao T, Zhang S-P, Wang J-F, Liu L, Wang Y, Cao Z-Y, Hu Q-K, Yuan W-J, Lin L. TLR3 contributes to persistent autophagy and heart failure in mice after myocardial infarction. J Cell Mol Med. 2018;22(1):395–408.

    Article  CAS  PubMed  Google Scholar 

  53. Lu C, Ren D, Wang X, Ha T, Liu L, Lee EJ, Hu J, Kalbfleisch J, Gao X, Kao R. Toll-like receptor 3 plays a role in myocardial infarction and ischemia/reperfusion injury. Biochim Biophys Acta (BBA) - Mol Basis Dis 2014;1842(1):22–31.

  54. Chen E, Chen C, Niu Z, Gan L, Wang Q, Li M, Cai X, Gao R, Katakam S, Chen H, Zhang S. Poly (I: C) preconditioning protects the heart against myocardial ischemia/reperfusion injury through TLR3/PI3K/Akt-dependent pathway. Signal Transduct Target Ther. 2020;5(1):1–15.

    Article  CAS  Google Scholar 

  55. Wu B, Ni H, Li J, Zhuang X, Zhang J, Qi Z, Chen Q, Wen Z, Shi H, Luo X, Jin B. The impact of circulating mitochondrial DNA on cardiomyocyte apoptosis and myocardial injury after TLR4 activation in experimental autoimmune myocarditis. Cell Physiol Biochem. 2017;42(2):713–28. https://doi.org/10.1159/000477889.

    Article  CAS  PubMed  Google Scholar 

  56. Jenke A, Wilk S, Poller W, Eriksson U, Valaperti A, Rauch BH, Stroux A, Liu P, Schultheiss H-P, Scheibenbogen C, Skurk C. Adiponectin protects against Toll-like receptor 4-mediated cardiac inflammation and injury. Cardiovasc Res. 2013;99(3):422–31. https://doi.org/10.1093/cvr/cvt118.

    Article  CAS  PubMed  Google Scholar 

  57. Satoh M, Shimoda Y, Maesawa C, Akatsu T, Ishikawa Y, Minami Y, Hiramori K, Nakamura M. Activated Toll-like receptor 4 in monocytes is associated with heart failure after acute myocardial infarction. Int J Cardiol. 2006;109(2):226–34.

    Article  PubMed  Google Scholar 

  58. Yang J, Jin L, Ding J, Zhou Y, Yang J. Expression of Toll-like receptor 4 on peripheral blood mononuclear cells and its effects on patients with acute myocardial infarction treated with thrombolysis. Arch Med Res. 2010;41(6):423–9.

    Article  CAS  PubMed  Google Scholar 

  59. Frangogiannis NG, Perrard JL, Mendoza LH, Burns AR, Lindsey ML, Ballantyne CM, Michael LH, Smith CW, Entman ML. Stem cell factor induction is associated with mast cell accumulation after canine myocardial ischemia and reperfusion. Circulation. 1998;98(7):687–98.

    Article  CAS  PubMed  Google Scholar 

  60. Yang R, Song Z, Wu S, Wei Z, Xu Y, Shen X. Toll-like receptor 4 contributes to a myofibroblast phenotype in cardiac fibroblasts and is associated with autophagy after myocardial infarction in a mouse model. Atherosclerosis. 2018;279:23–31.

    Article  CAS  PubMed  Google Scholar 

  61. Liu L, Wang Y, Cao Z-Y, Wang M-M, Liu X-M, Gao T, Hu Q-K, Yuan W-J, Lin L. Up-regulated TLR 4 in cardiomyocytes exacerbates heart failure after long-term myocardial infarction. J Cell Mol Med. 2015;19(12):2728–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Shimamoto A, Chong AJ, Yada M, Shomura S, Takayama H, Fleisig AJ, Agnew ML, Hampton CR, Rothnie CL, Spring DJ. Inhibition of Toll-like receptor 4 with eritoran attenuates myocardial ischemia-reperfusion injury. Circulation. 2006;114(1_supplement):I–270.

    Article  CAS  Google Scholar 

  63. Maekawa Y, Mizue N, Chan A, Shi Y, Liu Y, Dawood S, Chen M, Dawood F, De Couto G, Li GH. Survival and cardiac remodeling after myocardial infarction are critically dependent on the host innate immune interleukin-1 receptor-associated kinase-4 signaling: a regulator of bone marrow-derived dendritic cells. Circulation. 2009;120(14):1401–14.

    Article  CAS  PubMed  Google Scholar 

  64. Feng Y, Zhao H, Xu X, Buys ES, Raher MJ, Bopassa JC, Thibault H, Scherrer-Crosbie M, Schmidt U, Chao W. Innate immune adaptor MyD88 mediates neutrophil recruitment and myocardial injury after ischemia-reperfusion in mice. Am J Physiol Heart Circ Physiol. 2008;295(3):H1311–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Fujio Y, Nguyen T, Wencker D, Kitsis RN, Walsh K. Akt promotes survival of cardiomyocytes in vitro and protects against ischemia-reperfusion injury in mouse heart. Circulation. 2000;101(6):660–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wang Y, Hu H, Yin J, Shi Y, Tan J, Zheng L, Wang C, Li X, Xue M, Liu J, Wang Y. TLR4 participates in sympathetic hyperactivity post-MI in the PVN by regulating NF-κB pathway and ROS production. Redox Biol. 2019;24: 101186. https://doi.org/10.1016/j.redox.2019.101186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Fu H, Shuai W, Kong B, Jiang X, Huang H. MD1 Depletion predisposes to ventricular arrhythmias in the setting of myocardial infarction. Heart Lung Circ. 2021;30(6):869–81. https://doi.org/10.1016/j.hlc.2020.09.938.

    Article  PubMed  Google Scholar 

  68. Zhu X, Zhao H, Graveline AR, Buys ES, Schmidt U, Bloch KD, Rosenzweig A, Chao W. MyD88 and NOS2 are essential for Toll-like receptor 4-mediated survival effect in cardiomyocytes. Am J Physiol Heart Circ Physiol. 2006;291(4):H1900–9.

    Article  CAS  PubMed  Google Scholar 

  69. Zhao P, Wang J, He L, Ma H, Zhang X, Zhu X, Dolence EK, Ren J, Li J. Deficiency in TLR4 signal transduction ameliorates cardiac injury and cardiomyocyte contractile dysfunction during ischemia. J Cell Mol Med. 2009;13(8a):1513–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Timmers L, Sluijter JP, van Keulen JK, Hoefer IE, Nederhoff MG, Goumans M-J, Doevendans PA, van Echteld CJ, Joles JA, Quax PH. Toll-like receptor 4 mediates maladaptive left ventricular remodeling and impairs cardiac function after myocardial infarction. Circ Res. 2008;102(2):257–64.

    Article  CAS  PubMed  Google Scholar 

  71. Oyama J, Blais C, Liu X, Pu M, Kobzik L, Kelly RA, Bourcier T. Reduced myocardial ischemia-reperfusion injury in Toll-like receptor 4-deficient mice. Circulation. 2004;109(6):784–9. https://doi.org/10.1161/01.CIR.0000112575.66565.84.

    Article  CAS  PubMed  Google Scholar 

  72. Chong AJ, Shimamoto A, Hampton CR, Takayama H, Spring DJ, Rothnie CL, Yada M, Pohlman TH, Verrier ED. Toll-like receptor 4 mediates ischemia/reperfusion injury of the heart. J Thorac Cardiovasc Surg. 2004;128(2):170–9. https://doi.org/10.1016/j.jtcvs.2003.11.036.

    Article  CAS  PubMed  Google Scholar 

  73. Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, Brohi K, Itagaki K, Hauser CJ. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464(7285):104–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Shintani Y, Kapoor A, Kaneko M, Smolenski RT, D’Acquisto F, Coppen SR, Harada-Shoji N, Lee HJ, Thiemermann C, Takashima S. TLR9 mediates cellular protection by modulating energy metabolism in cardiomyocytes and neurons. Proc Natl Acad Sci. 2013;110(13):5109–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Duerr GD, Wu S, Schneider ML, Marggraf V, Weisheit CK, Velten M, Verfuerth L, Frede S, Boehm O, Treede H, Dewald O. CpG postconditioning after reperfused myocardial infarction is associated with modulated inflammation, less apoptosis, and better left ventricular function. Am J Physiol Heart Circ Physiol. 2020;319(5):H995–1007.

    Article  CAS  PubMed  Google Scholar 

  76. Tian Y, Charles EJ, Yan Z, Wu D, French BA, Kron IL, Yang Z. The myocardial infarct-exacerbating effect of cell-free DNA is mediated by the high-mobility group box 1–receptor for advanced glycation end products–Toll-like receptor 9 pathway. J Thorac Cardiovasc Surg. 2019;157(6):2256–69.

    Article  CAS  PubMed  Google Scholar 

  77. Liu F-Y, Fan D, Yang Z, Tang N, Guo Z, Ma S-Q, Ma Z-G, Wu H-M, Deng W, Tang Q-Z. TLR9 is essential for HMGB1-mediated post-myocardial infarction tissue repair through affecting apoptosis, cardiac healing, and angiogenesis. Cell Death Dis. 2019;10(7):1–16.

    Article  Google Scholar 

  78. Omiya S, Omori Y, Taneike M, Protti A, Yamaguchi O, Akira S, Shah AM, Nishida K, Otsu K. Toll-like receptor 9 prevents cardiac rupture after myocardial infarction in mice independently of inflammation. Am J Physiol Heart Circ Physiol. 2016;311(6):H1485–97.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Ohm IK, Gao E, Belland Olsen M, Alfsnes K, Bliksøen M, Øgaard J, Ranheim T, Nymo SH, Holmen YD, Aukrust P, Yndestad A, Vinge LE. Toll-like receptor 9-activation during onset of myocardial ischemia does not influence infarct extension. PLoS ONE. 2014;9(8): e104407. https://doi.org/10.1371/journal.pone.0104407.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Enquobahrie DA, Smith NL, Bis JC, Carty CL, Rice KM, Lumley T, Hindorff LA, Lemaitre RN, Williams MA, Siscovick DS. Cholesterol ester transfer protein, interleukin-8, peroxisome proliferator activator receptor alpha, and Toll-like receptor 4 genetic variations and risk of incident nonfatal myocardial infarction and ischemic stroke. Am J Cardiol. 2008;101(12):1683–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Blasius AL, Beutler B. Intracellular Toll-like receptors. Immunity. 2010;32(3):305–15.

    Article  CAS  PubMed  Google Scholar 

  82. Zhang S-P, Yang R-H, Shang J, Gao T, Wang R, Peng X-D, Miao X, Pan L, Yuan W-J, Lin L. FOXC1 up-regulates the expression of Toll-like receptors in myocardial ischaemia. J Cell Mol Med. 2019;23(11):7566–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Roelofs MF, Joosten LAB, Abdollahi-Roodsaz S, van Lieshout AWT, Sprong T, van den Hoogen FH, van den Berg WB, Radstake TRDJ. The expression of Toll-like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of Toll-like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells. Arthritis Rheum. 2005;52(8):2313–22. https://doi.org/10.1002/art.21278.

    Article  CAS  PubMed  Google Scholar 

  84. Desnues B, Macedo AB, Roussel-Queval A, Bonnardel J, Henri S, Demaria O, Alexopoulou L. TLR8 on dendritic cells and TLR9 on B cells restrain TLR7-mediated spontaneous autoimmunity in C57BL/6 mice. Proc Natl Acad Sci U S A. 2014;111(4):1497–502. https://doi.org/10.1073/pnas.1314121111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Frantz S, Kobzik L, Kim YD, Fukazawa R, Medzhitov R, Lee RT, Kelly RA. Toll4 (TLR4) Expression in cardiac myocytes in normal and failing myocardium. J Clin Invest. 1999;104(3):271–80. https://doi.org/10.1172/JCI6709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. De Paola M, Mariani A, Bigini P, Peviani M, Ferrara G, Molteni M, Gemma S, Veglianese P, Castellaneta V, Boldrin V, Rossetti C, Chiabrando C, Forloni G, Mennini T, Fanelli R. Neuroprotective effects of Toll-like receptor 4 antagonism in spinal cord cultures and in a mouse model of motor neuron degeneration. Mol Med. 2012;18:971–81. https://doi.org/10.2119/molmed.2012.00020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Nihon-Yanagi Y, Wakayama M, Tochigi N, Saito F, Ogata H, Shibuya K. Immunohistochemical analysis of Toll-like receptors, MyD88, and TRIF in human papillary thyroid carcinoma and anaplastic thyroid carcinoma. J Thyroid Res 2021;e4226491. https://doi.org/10.1155/2021/4226491.

  88. Fallach R, Shainberg A, Avlas O, Fainblut M, Chepurko Y, Porat E, Hochhauser E. Cardiomyocyte Toll-like receptor 4 is involved in heart dysfunction following septic shock or myocardial ischemia. J Mol Cell Cardiol. 2010;48(6):1236–44. https://doi.org/10.1016/j.yjmcc.2010.02.020.

    Article  CAS  PubMed  Google Scholar 

  89. Boekholdt SM, Agema WRP, Peters RJG, Zwinderman AH, van der Wall EE, Reitsma PH, Kastelein JJP, Jukema JW, REgression GRowth Evaluation Statin Study Group. Variants of Toll-like receptor 4 modify the efficacy of statin therapy and the risk of cardiovascular events. Circulation. 2003;107(19):2416–21. https://doi.org/10.1161/01.CIR.0000068311.40161.28.

    Article  CAS  PubMed  Google Scholar 

  90. Takeda K, Akira S. Toll-like receptors. Curr Protoc Immunol. 2015;109:14.12.1-14.12.10. https://doi.org/10.1002/0471142735.im1412s109.

    Article  Google Scholar 

  91. Jia F, Chen L, Fang L, Chen W. IRAK-M deletion aggravates acute inflammatory response and mitochondrial respiratory dysfunction following myocardial infarction: a bioinformatics analysis. J Proteome. 2022;15(257):104512. https://doi.org/10.1016/j.jprot.2022.104512.

    Article  CAS  Google Scholar 

  92. Nilsen NJ, Vladimer GI, Stenvik J, Orning MPA, Zeid-Kilani MV, Bugge M, Bergstroem B, Conlon J, Husebye H, Hise AG. A role for the adaptor proteins TRAM and TRIF in Toll-like receptor 2 signaling. J Biol Chem. 2015;290(6):3209–22.

    Article  CAS  PubMed  Google Scholar 

  93. Li X, Jiang S, Tapping RI. Toll-like receptor signaling in cell proliferation and survival. Cytokine. 2010;49(1):1–9.

    Article  CAS  PubMed  Google Scholar 

  94. Kawasaki T, Kawai T. Toll-like receptor signaling pathways. Front Immunol. 2014;5:461.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Li Z, Nguyen TT, Valaperti A. Human cardiac fibroblasts produce pro-inflammatory cytokines upon TLRs and RLRs stimulation. Mol Cell Biochem. 2021. https://doi.org/10.1007/s11010-021-04157-7.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Fukui D, Yasukawa H, Sugi Y, Oba T, Nagata T, Kyogoku S, Futamata N, Yokoyama T, Yokoyama S, Kai H, Ueno T, Kage M, Imaizumi T. Transient reduction and activation of circulating dendritic cells in patients with acute myocardial infarction. Int J Cardiol. 2012;160(3):216–9. https://doi.org/10.1016/j.ijcard.2012.06.070.

    Article  PubMed  Google Scholar 

  97. Lin L, Knowlton AA. Innate immunity and cardiomyocytes in ischemic heart disease. Life Sci. 2014;100(1):1–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Goulopoulou S, McCarthy CG, Webb RC. Toll-like receptors in the vascular system: sensing the dangers within. Pharmacol Rev. 2016;68(1):142–67.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Gao Y, Sun Y, Ercan-Sencicek AG, King JS, Akerberg BN, Ma Q, Kontaridis MI, Pu WT, Lin Z. YAP/TEAD1 complex is a default repressor of cardiac Toll-like receptor genes. Int J Mol Sci. 2021;22(13):6649. https://doi.org/10.3390/ijms22136649.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Ionita MG, Arslan F, De Kleijn DP, Pasterkamp G. Endogenous inflammatory molecules engage Toll-like receptors in cardiovascular disease. J Innate Immun. 2010;2(4):307–15.

    Article  CAS  PubMed  Google Scholar 

  101. Jaén RI, Val-Blasco A, Prieto P, Gil-Fernández M, Smani T, López-Sendón JL, Delgado C, Boscá L, Fernández-Velasco M. Innate immune receptors, key actors in cardiovascular diseases. Basic to Translational Science. 2020;5(7):735–49.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Yu, L.; Feng, Z. The role of Toll-like receptor signaling in the progression of heart failure. Mediat Inflamm 2018;2018.

  103. Zhang W, Lavine KJ, Epelman S, Evans SA, Weinheimer CJ, Barger PM, Mann DL. Necrotic myocardial cells release damage-associated molecular patterns that provoke fibroblast activation in vitro and trigger myocardial inflammation and fibrosis in vivo. J Am Heart Assoc. 2015;4(6): e001993. https://doi.org/10.1161/JAHA.115.001993.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Katare PB, Nizami HL, Paramesha B, Dinda AK, Banerjee SK. Activation of Toll like receptor 4 (TLR4) promotes cardiomyocyte apoptosis through SIRT2 dependent P53 deacetylation. Sci Rep. 2020;10(1):19232. https://doi.org/10.1038/s41598-020-75301-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Biemmi V, Milano G, Ciullo A, Cervio E, Burrello J, Cas MD, Paroni R, Tallone T, Moccetti T, Pedrazzini G, Longnus S, Vassalli G, Barile L. Inflammatory extracellular vesicles prompt heart dysfunction via TRL4-dependent NF-ΚB activation. Theranostics. 2020;10(6):2773. https://doi.org/10.7150/thno.39072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Sopasakis VR, Sandstedt J, Johansson M, Lundqvist A, Bergström G, Jeppsson A, Hultén LM. Toll-like receptor-mediated inflammation markers are strongly induced in heart tissue in patients with cardiac disease under both ischemic and non-ischemic conditions. Int J Cardiol. 2019;293:238–47.

    Article  Google Scholar 

  107. Tang Y, Xu Z, Chen X, Wang N, Deng X, Peng L, Chen Q, Cai H. Effects of enalapril on TLR2/NF-κB signaling pathway and inflammatory factors in rabbits with chronic heart failure. Evidence-Based Complementary and Alternative Medicine. 2021. https://doi.org/10.1155/2021/9594607.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Frantz S, Kelly RA, Bourcier T. Role of TLR-2 in the activation of nuclear factor kappaB by oxidative stress in cardiac myocytes. J Biol Chem. 2001;276(7):5197–203. https://doi.org/10.1074/jbc.M009160200.

    Article  CAS  PubMed  Google Scholar 

  109. Gu Y, Hu X, Ge PB, Chen Y, Wu S, Zhang XW. CTRP1 aggravates cardiac dysfunction post myocardial infarction by modulating TLR4 in macrophages. Front Immunol. 2021;12:1652.

    Article  Google Scholar 

  110. Cai S, Rohailla S, Peng J, Zeng C, Li J, Redington A. Loss of TLR4 in a murine model of left anterior descending myocardial infarction modifies early remodeling, but does not provide long-term benefit. Int J Cardiol. 2016;212:118–20.

    Article  PubMed  Google Scholar 

  111. Parapanov R, Lugrin J, Rosenblatt-Velin N, Feihl F, Waeber B, Milano G, Vergely C, Li N, Pacher P, Liaudet L. Toll-like receptor 5 deficiency exacerbates cardiac injury and inflammation induced by myocardial ischaemia-reperfusion in the mouse. Clin Sci. 2015;129(2):187–98.

    Article  CAS  Google Scholar 

  112. Hasham MG, Baxan N, Stuckey DJ, Branca J, Perkins B, Dent O, Duffy T, Hameed TS, Stella SE, Bellahcene M. Systemic autoimmunity induced by the TLR7/8 agonist resiquimod causes myocarditis and dilated cardiomyopathy in a new mouse model of autoimmune heart disease. Dis Model Mech. 2017;10(3):259–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Feng Y, Chen H, Cai J, Zou L, Yan D, Xu G, Li D, Chao W. Cardiac RNA induces inflammatory responses in cardiomyocytes and immune cells via Toll-like receptor 7 signaling. J Biol Chem. 2015;290(44):26688–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Pagni PP, Traub S, Demaria O, Chasson L, Alexopoulou L. Contribution of TLR7 and TLR9 signaling to the susceptibility of MyD88-deficient mice to myocarditis. Autoimmunity. 2010;43(4):275–87.

    Article  CAS  PubMed  Google Scholar 

  115. Fang L, Gao X-M, Moore X-L, Kiriazis H, Su Y, Ming Z, Lim YL, Dart AM, Du X-J. Differences in inflammation, MMP activation and collagen damage account for gender difference in murine cardiac rupture following myocardial infarction. J Mol Cell Cardiol. 2007;43(5):535–44.

    Article  CAS  PubMed  Google Scholar 

  116. Becher PM, Hinrichs S, Fluschnik N, Hennigs JK, Klingel K, Blankenberg S, Westermann D, Lindner D. Role of Toll-like receptors and interferon regulatory factors in different experimental heart failure models of diverse etiology: IRF7 as novel cardiovascular stress-inducible factor. PLoS ONE. 2018;13(3): e0193844.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. de Kleijn DP, Chong SY, Wang X, Yatim SMJ, Fairhurst A-M, Vernooij F, Zharkova O, Chan MY, Foo RS, Timmers L. Toll-like receptor 7 deficiency promotes survival and reduces adverse left ventricular remodelling after myocardial infarction. Cardiovasc Res. 2019;115(12):1791–803.

    Article  PubMed  CAS  Google Scholar 

  118. Anwar MA, Basith S, Choi S. Negative regulatory approaches to the attenuation of Toll-like receptor signaling. Exp Mol Med. 2013;45(2): e11. https://doi.org/10.1038/emm.2013.28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Prescott JA, Mitchell JP, Cook SJ. Inhibitory feedback control of NF-κB signalling in health and disease. Biochem J. 2021;16(478):2619–64.

    Article  Google Scholar 

  120. Saxena A, Shinde AV, Haque Z, Wu YJ, Chen W, Su Y, Frangogiannis NG. The role of interleukin receptor associated kinase (IRAK)-M in regulation of myofibroblast phenotype in vitro, and in an experimental model of non-reperfused myocardial infarction. J Mol Cell Cardiol. 2015;89:223–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Christia P, Frangogiannis NG. Targeting inflammatory pathways in myocardial infarction. Eur J Clin Invest. 2013;43(9):986–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Parizadeh SM, Ghandehari M, Heydari-Majd M, Seifi S, Mardani R, Parizadeh SM, Ghayour-Mobarhan M, Ferns GA, Hassanian SM, Avan A. Toll-like receptors signaling pathways as a potential therapeutic target in cardiovascular disease. Curr Pharm Des. 2018;24(17):1887–98.

    Article  CAS  PubMed  Google Scholar 

  123. Juntang L, Vijay K, Xinjie L. Essential roles of Toll-like receptors in atherosclerosis. Curr Med Chem. 2016;23(5):431–54.

    Article  CAS  Google Scholar 

  124. Birks EJ, Felkin LE, Banner NR, Khaghani A, Barton PJ, Yacoub MH. Increased Toll-like receptor 4 in the myocardium of patients requiring left ventricular assist devices. J Heart Lung Transplant. 2004;23(2):228–35.

    Article  PubMed  Google Scholar 

  125. Li C, Ha T, Kelley J, Gao X, Qiu Y, Kao RL, Browder W, Williams DL. Modulating Toll-like receptor mediated signaling by (1→ 3)-β-D-glucan rapidly induces cardioprotection. Cardiovasc Res. 2004;61(3):538–47.

    Article  CAS  PubMed  Google Scholar 

  126. Sun Y, Huang J, Song K. BET protein inhibition mitigates acute myocardial infarction damage in rats via the TLR4/TRAF6/NF-κB pathway. Exp Ther Med. 2015;10(6):2319–24. https://doi.org/10.3892/etm.2015.2789.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Ramirez-Carracedo R, Tesoro L, Hernandez I, Diez-Mata J, Piñeiro D, Hernandez-Jimenez M, Zamorano JL, Zaragoza C. Targeting TLR4 with ApTOLL improves heart function in response to coronary ischemia reperfusion in pigs undergoing acute myocardial infarction. Biomolecules. 2020;10(8):1167. https://doi.org/10.3390/biom10081167.

    Article  CAS  PubMed Central  Google Scholar 

  128. Fujiwara M, Matoba T, Koga JI, Okahara A, Funamoto D, Nakano K, Tsutsui H, Egashira K. Nanoparticle incorporating Toll-like receptor 4 inhibitor attenuates myocardial ischaemia–reperfusion injury by inhibiting monocyte-mediated inflammation in mice. Cardiovasc Res. 2019;115(7):1244–55. https://doi.org/10.1093/cvr/cvz066.

    Article  CAS  PubMed  Google Scholar 

  129. Louwe MC, Karper JC, de Vries MR, Nossent AY, Bastiaansen AJNM, van der Hoorn JWA, van Dijk KW, Rensen PCN, Steendijk P, Smit JWA, Quax PHA. RP105 deficiency aggravates cardiac dysfunction after myocardial infarction in mice. Int J Cardiol. 2014;176(3):788–93. https://doi.org/10.1016/j.ijcard.2014.07.086.

    Article  CAS  PubMed  Google Scholar 

  130. Zaafan MA, Abdelhamid AM. The cardioprotective effect of astaxanthin against isoprenaline-induced myocardial injury in rats: involvement of TLR4/NF-κB signaling pathway. Eur Rev Med Pharmacol Sci. 2021;25(11):4099–105.

    CAS  PubMed  Google Scholar 

  131. Shi H, Zhou P, Gao G, Liu PP, Wang SS, Song R, Zou YY, Yin G, Wang L. Astragaloside IV prevents acute myocardial infarction by inhibiting the TLR4/MyD88/NF-κB signaling pathway. J Food Biochem. 2021;45(7): e13757. https://doi.org/10.1111/jfbc.13757.

    Article  CAS  PubMed  Google Scholar 

  132. Sun JH, Yang HX, Yao TT, Li Y, Ruan L, Xu GR, Zhang C, Guo GX, Li AY. Gentianella acuta prevents acute myocardial infarction induced by isoproterenol in rats via inhibition of galectin-3/TLR4/MyD88/NF-кB inflammatory signalling. Inflammopharmacology. 2021;29(1):205–19.

    Article  CAS  PubMed  Google Scholar 

  133. Wang X, Guo D, Li W, Zhang Q, Jiang Y, Wang Q, Li C, Qiu Q, Wang Y. Danshen (Salvia miltiorrhiza) restricts MD2/TLR4-MyD88 complex formation and signalling in acute myocardial infarction-induced heart failure. J Cell Mol Med. 2020;24(18):10677–92. https://doi.org/10.1111/jcmm.15688.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Chen F, Chen ZQ, Zhong GL, Zhu JJ. Nicorandil inhibits TLR4/MyD88/NF-κB/NLRP3 signaling pathway to reduce pyroptosis in rats with myocardial infarction. Exp Biol Med. 2021;246(17):19381947. https://doi.org/10.1177/15353702211013444.

    Article  CAS  Google Scholar 

  135. Abdelzaher WY, Ahmed SM, Welson NN, Alsharif KF, Batiha GES, Labib DAA. Dapsone ameliorates isoproterenol-induced myocardial infarction via Nrf2/HO-1; TLR4/TNF-α signaling pathways and the suppression of oxidativestress, inflammation, and apoptosis in rats. Front Pharmacol. 2021;12:1230. https://doi.org/10.3389/fphar.2021.669679.

    Article  CAS  Google Scholar 

  136. Li H, Yang H, Wang D, Zhang L, Ma T. Peroxiredoxin2 (Prdx2) reduces oxidative stress and apoptosis of myocardial cells induced by acute myocardial infarction by inhibiting the TLR4/nuclear factor kappa B (NF-κB) signaling pathway. Med Sci Monit. 2020;26:e926281–91. https://doi.org/10.12659/MSM.926281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Cao Z, Ren D, Ha T, Liu L, Wang X, Kalbfleisch J, Gao X, Kao R, Williams D, Li C. CpG-ODN, the TLR9 agonist, attenuates myocardial ischemia/reperfusion injury: involving activation of PI3K/Akt signaling. Biochim Biophys Acta. 2013;1832(1):96–104.

    Article  CAS  PubMed  Google Scholar 

  138. Yonebayashi S, Tajiri K, Murakoshi N, Xu D, Li S, Feng D, Okabe Y, Yuan Z, Song Z, Aonuma K, Shibuya A. MAIR-II deficiency ameliorates cardiac remodelling post-myocardial infarction by suppressing TLR9-mediated macrophage activation. J Cell Mol Med. 2020;24(24):14481–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Savoji H, Mohammadi MH, Rafatian N, Toroghi MK, Wang EY, Zhao Y, Korolj A, Ahadian S, Radisic M. Cardiovascular disease models: a game changing paradigm in drug discovery and screening. Biomaterials. 2019;198:3–26.

    Article  CAS  PubMed  Google Scholar 

  140. Boukhvalova MS, Prince GA, Soroush L, Harrigan DC, Vogel SN, Blanco JCG. The TLR4 agonist, monophosphoryl lipid A, attenuates the cytokine storm associated with respiratory syncytial virus vaccine-enhanced disease. Vaccine. 2006;24(23):5027–35. https://doi.org/10.1016/j.vaccine.2006.03.064.

    Article  CAS  PubMed  Google Scholar 

  141. Reiter MJ, Man TLT, Miller RL, Weeks CE, Tomai MA. Cytokine induction in mice by the immunomodulator imiquimod. J Leukoc Biol. 1994;55(2):234–40. https://doi.org/10.1002/jlb.55.2.234.

    Article  CAS  PubMed  Google Scholar 

  142. Lamm DL, Blumenstein BA, Crawford ED, Montie JE, Scardino P, Grossman HB, Stanisic TH, Smith JA, Sullivan J, Sarosdy MF. A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional-cell carcinoma of the bladder. N Engl J Med. 1991;325(17):1205–9. https://doi.org/10.1056/NEJM199110243251703.

    Article  CAS  PubMed  Google Scholar 

  143. Wada H, Isobe M, Kakimi K, Mizote Y, Eikawa S, Sato E, Takigawa N, Kiura K, Tsuji K, Iwatsuki K. Vaccination with NY-ESO-1 overlapping peptides mixed with Picibanil OK-432 and montanide ISA-51 in patients with cancers expressing the NY-ESO-1 antigen. J Immunother. 2014;37(2):84–92.

    Article  CAS  PubMed  Google Scholar 

  144. Tilea I, Varga A, Serban RC. Past, present, and future of blood biomarkers for the diagnosis of acute myocardial infarction—promises and challenges. Diagnostics (Basel). 2021;11(5):881. https://doi.org/10.3390/diagnostics11050881.

    Article  CAS  Google Scholar 

  145. Wu Y, Pan N, An Y, Xu M, Tan L, Zhang L. Diagnostic and prognostic biomarkers for myocardial infarction. Front Cardiovasc Med 2022, 7, Accessed: [Online]. https://www.frontiersin.org/article/, https://doi.org/10.3389/fcvm.2020.617277

  146. Zhang S, Liu W, Liu X, Qi J, Deng C. Biomarkers identification for acute myocardial infarction detection via weighted gene co-expression network analysis. Medicine (Baltimore). 2017;96(47): e8375. https://doi.org/10.1097/MD.0000000000008375.

    Article  Google Scholar 

  147. Zhang P, Shao L, Ma J. Toll-Like receptors 2 and 4 predict new-onset atrial fibrillation in acute myocardial infarction patients. Int Heart J. 2018;59(1):64–70. https://doi.org/10.1536/ihj.17-084.

    Article  CAS  PubMed  Google Scholar 

  148. Shao L, Zhang P, Zhang Y, Lu Q, Ma A. TLR3 and TLR4 as potential clinically biomarkers of cardiovascular risk in coronary artery disease (CAD) patients. Heart Vessels. 2014;29(5):690–8. https://doi.org/10.1007/s00380-013-0421-3.

    Article  PubMed  Google Scholar 

  149. Bhagat S, Biswas I, Alam MI, Khan M, Khan GA. Key role of extracellular RNA in hypoxic stress induced myocardial injury. PLoS ONE. 2021;16(12): e0260835. https://doi.org/10.1371/journal.pone.0260835.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Mirzaoglu C, Kivrak T, Balin M, Kobat MA, Dogdu O, Karaca I. Is there a correlation between systolic heart failure and levels of toll-like receptor-5 and N-terminal pro-B-type natriuretic peptide? Int J Cardiovasc Acad. 2018;4(4):65. https://doi.org/10.4103/IJCA.IJCA_41_18.

    Article  Google Scholar 

  151. Huang Z, Liu Y, Liang L, Liu W, Sooranna SR, Mo J, Liu L, Li Z, Li K, Guo J. Correlation between coronary stenosis and Toll-like receptors 2 and 4 levels in Chinese Zhuang patients with coronary heart disease. Exp Ther Med. 2019;18(3):2346–52. https://doi.org/10.3892/etm.2019.7805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Tapp LD, Shantsila E, Wrigley BJ, Montoro-Garcia S, Lip GYH. TLR4 expression on monocyte subsets in myocardial infarction. J Intern Med. 2013;273(3):294–305. https://doi.org/10.1111/joim.12011.

    Article  CAS  PubMed  Google Scholar 

  153. Bochaton T, Paccalet A, Jeantet P, Crola Da Silva C, Cartier R, Prieur C, Jossan C, Bonnefoy-Cudraz E, Mewton N, Ovize M. Heat shock protein 70 as a biomarker of clinical outcomes after STEMI. J Am Coll Cardiol. 2020;75(1):122–4.

    Article  CAS  PubMed  Google Scholar 

  154. Savas G, Kalay N, Altin P, Dursun GK, Cetin M, Aytekin M. Hyaluronan as a promising biomarker for myocardial damage. Tohoku J Exp Med. 2019;248(2):99–106.

    Article  CAS  PubMed  Google Scholar 

  155. Li X, Guo D, Chen Y, Hu Y. Toll-like receptors/TNF-α pathway crosstalk and impact on different sites of recurrent myocardial infarction in elderly patients. Biomed Res Int. 2022. https://doi.org/10.1155/2022/1280350.

    Article  PubMed  PubMed Central  Google Scholar 

  156. Li M, Chen F, Zhang Y, Xiong Y, Li Q, Huang H. Identification of post-myocardial infarction blood expression signatures using multiple feature selection strategies. Front Physiol 2020;483. https://doi.org/10.3389/fphys.2020.00483.

  157. Zhang Q, Wang L, Wang S, Cheng H, Xu L, Pei G, Wang Y, Fu C, Jiang Y, He C, Wei Q. Signaling pathways and targeted therapy for myocardial infarction. Signal Transduct Target Ther. 2022;7(1):1–38. https://doi.org/10.1038/s41392022-00925.

    Article  Google Scholar 

  158. Turner NA. Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs). J Mol Cell Cardiol. 2016;94:189–200.

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (No. 81670311) and the Natural Science Foundation of Henan Province (No. 182300410010).

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  1. Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China

    Sumra Komal, Shu-Hui Wang, Li-Rong Zhang & Sheng-Na Han

  2. Department of Pharmacology, Mohi-Ud-Din Islamic Medical College, Azad Jammu & Kashmir, Mirpur, 10250, Pakistan

    Nimrah Komal & Ali Mujtaba

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Komal, S., Komal, N., Mujtaba, A. et al. Potential therapeutic strategies for myocardial infarction: the role of Toll-like receptors. Immunol Res 70, 607–623 (2022). https://doi.org/10.1007/s12026-022-09290-z

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