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Inflammation

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Attenuation of Sepsis-Induced Cardiomyopathy by Regulation of MicroRNA-23b Is Mediated Through Targeting of MyD88-Mediated NF-κB Activation

  • Chao Cao
  • Yan Zhang
  • Yanfen Chai
  • Lijun Wang
  • Chengfen Yin
  • Songtao Shou
  • Heng JinEmail author
ORIGINAL ARTICLE
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Abstract

Myocardial cell injury or cardiomyopathy is associated with excessive inflammatory response and apoptosis of cardiac myocytes during sepsis. MicroRNA-23b (miR-23b) is a multifunctional miRNA that is considered to regulate immunosuppression in sepsis. The aim of this study was to examine the effect of miR-23b on cardiomyopathy induced by sepsis and to explore the potential mechanism involved. Sprague-Dawley rats were subjected to cecal ligation and puncture (CLP), and the level of miR-23b at different time points was measured by quantitative real-time polymerase chain reaction (qPCR). Then, we overexpressed miR-23b in vivo and in vitro. The rats were subjected to CLP 7 days after transfection. Cardiac function, inflammatory response, and heart tissues were examined 3 days thereafter. In an in vitro experiment, H9C2 cardiomyoblasts were stimulated with lipopolysaccharide (LPS) after transfection of miR-23b, following which apoptosis and the level of NF-κB were analyzed. The expression of miR-23b was upregulated during polymicrobial sepsis, and transfection of miR-23b lentivirus improved the outcome of sepsis-induced cardiomyopathy by attenuating inflammatory responses and protecting against histopathological damage. In in vitro experiments, elevated miR-23b inhibited excessive apoptosis of cardiomyocytes, which may be because activation of the NF-κB signaling pathway was inhibited by the decreased levels of TRAF6 and IKKβ. Therefore, miR-23b improved sepsis-induced cardiomyopathy by attenuating the inflammatory response, suppressing apoptosis, and preventing NF-κB activation via targeted inhibition of TRAF6 and IκκB. These results indicated that miR-23b may represent a novel therapeutic approach for clinical treatment of sepsis-induced cardiomyopathy.

KEY WORDS

microRNA-23b sepsis-induced cardiomyopathy inflammatory response NF-κB TRAF6 IκκB 

Abbreviations

BNP

Brain natriuretic peptide

CK-MB

Creatine kinase-MB

CLP

Cecal ligation and puncture

CO

Cardiac output

EF

Ejection fraction

ELISA

Enzyme-linked immunosorbent assay

EMSA

Electrophoretic mobility shift assay

ICAM-1

Intercellular cell adhesion molecule 1

LPS

Lipopolysaccharide

MIF

Migration inhibitory factor

miR-23b

MicroRNA-23b

NF-κB

Nuclear factor kappaB

qPCR

Quantitative real-time polymerase chain reaction

SIC

Sepsis-induced cardiomyopathy

TLR

Toll-like receptor

VCAM-1

Vascular cell adhesion molecule 1

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Notes

Authors’ Contributions

CC performed experiments, analyzed data, prepared figures, and wrote the manuscript. YZ, LJW, YFC, and STS performed experiments and analyzed data. CFY performed the histological examination of the heart tissues. HJ designed experiments, analyzed data, prepared figures, and wrote the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 81871593 to YFC), Theory E Emergency Medical Research Fund of China (Grant No. R2015026 to CC), and Tianjin Medical University General Hospital Fund of China (Grant No. ZYYFY2015010 to CC, ZYYFY2016026 to YZ).

Compliance with Ethical Standards

Competing Interests

The authors declare that they have no conflicts of interest.

Ethics Approval and Consent to Participate

All experimental manipulations were undertaken in accordance with the Guide for the Care and Use of Medical Laboratory Animals (Ministry of Health, P.R. China, 1998), with the approval of the Scientific Investigation Board, Tianjin Medical University General Hospital, Tianjin, China.

Supplementary material

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ESM 1 (DOCX 13 kb)
10753_2019_958_MOESM1_ESM.docx (58 kb)
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References

  1. 1.
    Singer, M., C.S. Deutschman, C.W. Seymour, M. Shankar-Hari, D. Annane, M. Bauer, R. Bellomo, G.R. Bernard, J.D. Chiche, C.M. Coopersmith, R.S. Hotchkiss, M.M. Levy, J.C. Marshall, G.S. Martin, S.M. Opal, G.D. Rubenfeld, T. van der Poll, J.L. Vincent, and D.C. Angus. 2016. The third international consensus definitions for sepsis and septic shock (sepsis-3). Journal of the American Medical Association 315: 801–810.CrossRefGoogle Scholar
  2. 2.
    Gomez, E., M. Vercauteren, B. Kurtz, A. Ouvrard-Pascaud, P. Mulder, J.P. Henry, M. Besnier, A. Waget, R. Hooft Van Huijsduijnen, M.L. Tremblay, et al. 2012. Reduction of heart failure by pharmacological inhibition or gene deletion of protein tyrosine phosphatase 1B. Journal of Molecular and Cellular. 52 (6): 1257–1264.Google Scholar
  3. 3.
    Charpentier, J., C.E. Luyt, Y. Fulla, C. Vinsonneau, A. Cariou, S. Grabar, J.F. Dhainaut, J.P. Mira, and J.D. Chiche. 2004. Brain natriuretic peptide: a marker of myocardial dysfunction and prognosis during severe sepsis. Critical Care Medicine 32 (3): 660–665.CrossRefGoogle Scholar
  4. 4.
    Gille-Johnson, P., C. Smedman, L. Gudmundsdotter, A. Somell, K. Nihlmark, S. Paulie, J. Andersson, and B. Gårdlund. 2012. Circulating monocytes are not the major source of plasma cytokines in patients with sepsis. Shock 38 (6): 577–583.CrossRefGoogle Scholar
  5. 5.
    Vieillard-Baron, A., V. Caille, C. Charron, G. Belliard, B. Page, and F. Jardin. 2008. Actual incidence of global left ventricular hypokinesia in adult septic shock. Critical Care Medicine 36 (6): 1701–1706.CrossRefGoogle Scholar
  6. 6.
    Fleischmann, C., A. Scherag, N.K. Adhikari, C.S. Hartog, T. Tsaganos, P. Schlattmann, D.C. Angus, and K. Reinhart. 2016. International Forum of Acute Care Trialists: Assessment of global incidence and mortality of hospital-treated Sepsis. Current estimates and limitations. American Journal of Respiratory and Critical Care Medicine 193 (3): 259–272.CrossRefGoogle Scholar
  7. 7.
    Micek, S.T., C. McEvoy, M. McKenzie, N. Hampton, J.A. Doherty, and M.H. Kollef. 2013. Fluid balance and cardiac function in septic shock as predictors of hospital mortality. Critical Care 17 (5): R246.CrossRefGoogle Scholar
  8. 8.
    Antonucci, E., E. Fiaccadori, K. Donadello, F.S. Taccone, F. Franchi, and S. Scolletta. 2014. Myocardial depression in sepsis: from pathogenesis to clinical manifestations and treatment. Journal of Critical Care 29 (4): 500–511.CrossRefGoogle Scholar
  9. 9.
    Liu, Y.C., M.M. Yu, S.T. Shou, and Y.F. Chai. 2017. Sepsis-induced cardiomyopathy: mechanisms and treatments. Frontiers in Immunology 8 (1021).Google Scholar
  10. 10.
    Tsolaki, V., D. Makris, K. Mantzarlis, and E. Zakynthinos. 2017. Sepsis-induced cardiomyopathy: oxidative implications in the initiation and resolution of the damage. Oxidative Medicine and Cellular Longevity 2017: 7393525.CrossRefGoogle Scholar
  11. 11.
    Suffredini, A.F., R.E. Fromm, M.M. Parker, M. Brenner, J.A. Kovacs, R.A. Wesley, and J.E. Parrillo. 1989. The cardiovascular response of normal humans to the administration of endotoxin. The New England Journal of Medicine 321 (5): 280–287.CrossRefGoogle Scholar
  12. 12.
    Mann, M., A. Mehta, J.L. Zhao, K. Lee, G.K. Marinov, Y. Garcia-Flores, and D. Baltimore. 2017. An NF-κB-microRNA regulatory network tunes macrophage inflammatory responses. Nature Communications 8 (1): 851.CrossRefGoogle Scholar
  13. 13.
    Cao, C., C. Yin, S. Shou, J. Wang, L. Yu, X. Li, and Y. Chai. 2018. Ulinastatin protects against LPS-induced acute lung injury by attenuating TLR4/NF-κB pathway activation and reducing inflammatory mediators. Shock 50 (5): 595–605.CrossRefGoogle Scholar
  14. 14.
    Zou, L., Y. Feng, Y.J. Chen, R. Si, S. Shen, Q. Zhou, F. Ichinose, M. Scherrer-Crosbie, and W. Chao. 2010. Toll-like receptor 2 plays a critical role in cardiac dysfunction during polymicrobial sepsis. Critical Care Medicine 38 (5): 1335–1342.CrossRefGoogle Scholar
  15. 15.
    Gao, M., T. Ha, X. Zhang, L. Liu, X. Wang, J. Kelley, K. Singh, R. Kao, X. Gao, D. Williams, et al. 2010. Toll-like receptor 3 plays a central role in cardiac dysfunction during polymicrobial sepsis. Critical Care Medicine 40 (8): 2390–2399.CrossRefGoogle Scholar
  16. 16.
    Gao, M., T. Ha, X. Zhang, X. Wang, L. Liu, J. Kalbfleisch, K. Singh, D. Williams, and C. Li. 2013. The Toll-like receptor 9 ligand, CpG oligodeoxynucleotide, attenuates cardiac dysfunction in polymicrobial sepsis, involving activation of both phosphoinositide 3 kinase/Akt and extracellular-signal-related kinase signaling. The Journal of Infectious Diseases 207 (9): 1471–1479.CrossRefGoogle Scholar
  17. 17.
    Melton, C., R.L. Judson, and R. Blelloch. 2010. Opposing microRNA families regulate self-renewal in mouse embryonic stem cells. Nature 463 (7281): 621–626.CrossRefGoogle Scholar
  18. 18.
    Dvinge, H., A. Git, S. Gräf, M. Salmon-Divon, C. Curtis, A. Sottoriva, Y. Zhao, M. Hirst, J. Armisen, E.A. Miska, S.F. Chin, E. Provenzano, G. Turashvili, A. Green, I. Ellis, S. Aparicio, and C. Caldas. 2013. The shaping and functional consequences of the microRNA landscape in breast cancer. Nature 497 (7449): 378–382.CrossRefGoogle Scholar
  19. 19.
    Amaral, A.E.D., M.P. Rode, J. Cisilotto, T.E.D. Silva, J. Fischer, C. Matiollo, E.C. Morais Rateke, J.L. Narciso-Schiavon, L.L. Schiavon, and T.B. Creczynski-Pasa. 2018. MicroRNA profiles in serum samples from patients with stable cirrhosis and miRNA-21 as a predictor of transplant-free survival. Pharmacological Research 134: 179–192.CrossRefGoogle Scholar
  20. 20.
    Tacke, F., C. Roderburg, F. Benz, D.V. Cardenas, M. Luedde, H.J. Hippe, N. Frey, M. Vucur, J. Gautheron, A. Koch, C. Trautwein, and T. Luedde. 2014. Levels of circulating miR-133a are elevated in sepsis and predict mortality in critically ill patients. Critical Care Medicine 42 (5): 1096–1104.CrossRefGoogle Scholar
  21. 21.
    Ge, C., J. Liu, and S. Dong. 2018. miRNA-214 protects sepsis-induced myocardial injury. Shock 50 (1): 112–118.CrossRefGoogle Scholar
  22. 22.
    Ma, H., X. Wang, T. Ha, M. Gao, L. Liu, R. Wang, K. Yu, J.H. Kalbfleisch, R.L. Kao, D.L. Williams, and C. Li. 2016. MicroRNA-125b prevents cardiac dysfunction in polymicrobial sepsis by targeting TRAF6-mediated nuclear factor κB activation and p53-mediated apoptotic signaling. The Journal of Infectious Diseases 214 (11): 1773–1783.CrossRefGoogle Scholar
  23. 23.
    Wang, H., Y. Bei, S. Shen, P. Huang, J. Shi, J. Zhang, Q. Sun, Y. Chen, Y. Yang, T. Xu, X. Kong, and J. Xiao. 2016. miR-21-3p controls sepsis-associated cardiac dysfunction via regulating SORBS2. Journal of Molecular and Cellular Cardiology 94: 43–53.CrossRefGoogle Scholar
  24. 24.
    Grieco, F.A., G. Sebastiani, J. Juan-Mateu, O. Villate, L. Marroqui, L. Ladrière, K. Tugay, R. Regazzi, M. Bugliani, P. Marchetti, F. Dotta, and D.L. Eizirik. 2017. MicroRNAs miR-23a-3p, miR-23b-3p, and miR-149-5p regulate the expression of proapoptotic BH3-only proteins DP5 and PUMA in human pancreatic β-cells. Diabetes 66 (1): 100–112.CrossRefGoogle Scholar
  25. 25.
    Hu, R., and R.M. O’Connell. 2012. MiR-23b is a safeguard against autoimmunity. Nature Medicine 18 (7): 1009–1010, 2017.CrossRefGoogle Scholar
  26. 26.
    Zheng, J., H.Y. Jiang, J. Li, H.C. Tang, X.M. Zhang, X.R. Wang, J.T. Du, H.B. Li, and G. Xu. 2012. MicroRNA-23b promotes tolerogenic properties of dendritic cells in vitro through inhibiting Notch1/NF-κB signalling pathways. Allergy 67 (3): 362–370.CrossRefGoogle Scholar
  27. 27.
    Zhu, S., W. Pan, X. Song, Y. Liu, X. Shao, Y. Tang, D. Liang, D. He, H. Wang, W. Liu, Y. Shi, J.B. Harley, N. Shen, and Y. Qian. 2012. The microRNA miR-23b suppresses IL-17-associated autoimmune inflammation by targeting TAB2, TAB3 and IKK-alpha. Nature Medicine 18 (7): 1077–1086.CrossRefGoogle Scholar
  28. 28.
    Wu, M., J.T. Gu, B. Yi, Z.Z. Tang, and G.C. Tao. 2015. microRNA-23b regulates the expression of inflammatory factors in vascular endothelial cells during sepsis. Experimental and Therapeutic Medicine 9 (4): 1125–1132.CrossRefGoogle Scholar
  29. 29.
    Hoyt, C.C., S.M. Richardson-Burns, R.J. Goody, B.A. Robinson, R.L. Debiasi, and K.L. Tyler. 2005. Nonstructural protein sigma1s is a determinant of reovirus virulence and influences the kinetics and severity of apoptosis induction in the heart and central nervous system. Journal of Virology 79 (5): 2743–2753.CrossRefGoogle Scholar
  30. 30.
    Cao, C., C. Yin, Y. Chai, H. Jin, L. Wang, and S. Shou. 2018. Ulinastatin mediates suppression of regulatory T cells through TLR4/NF-κB signaling pathway in murine sepsis. International Immunopharmacology 64: 411–423.CrossRefGoogle Scholar
  31. 31.
    Hobai, I.A., J. Edgecomb, K. LaBarge, and W.S. Colucci. 2015. Dysregulation of intracellular calcium transporters in animal models of sepsis-induced cardiomyopathy. Shock 43 (1): 3–15.CrossRefGoogle Scholar
  32. 32.
    Zhang, H., H.Y. Wang, R. Bassel-Duby, D.L. Maass, W.E. Johnston, J.W. Horton, and W. Tao. 2007. Role of interleukin-6 in cardiac inflammation and dysfunction after burn complicated by sepsis. American Journal of Physiology. Heart and Circulatory Physiology 292 (5): H2408–H2416.CrossRefGoogle Scholar
  33. 33.
    Zhang, G., and S. Ghosh. 2001. Toll-like receptor-mediated NF-kappaB activation: a phylogenetically conserved paradigm in innate immunity. The Journal of Clinical Investigation 107 (1): 13–19.CrossRefGoogle Scholar
  34. 34.
    Sheehan, M., H.R. Wong, P.W. Hake, and B. Zingarelli. 2003. Parthenolide improves systemic hemodynamics and decreases tissue leukosequestration in rats with polymicrobial sepsis. Critical Care Medicine 31 (9): 2263–2270.CrossRefGoogle Scholar
  35. 35.
    Zheng, Z., H. Ma, X. Zhang, F. Tu, X. Wang, T. Ha, M. Fan, L. Liu, J. Xu, K. Yu, R. Wang, J. Kalbfleisch, R. Kao, D. Williams, and C. Li. 2017. Enhanced glycolytic metabolism contributes to cardiac dysfunction in polymicrobial sepsis. The Journal of Infectious Diseases 215 (9): 1396–1406.CrossRefGoogle Scholar
  36. 36.
    Brudecki, L., D.A. Ferguson, D. Yin, G.D. Lesage, C.E. McCall, and M. El Gazzar. 2012. Hematopoietic stem-progenitor cells restore immunoreactivity and improve survival in late sepsis. Infection and Immunity 80 (2): 602–611.CrossRefGoogle Scholar
  37. 37.
    Yoon, S.J., S.J. Kim, and S.M. Lee. 2017. Overexpression of HO-1 contributes to sepsis-induced immunosuppression by modulating the Th1/Th2 balance and regulatory T-cell function. The Journal of Infectious Diseases 215 (10): 1608–1618.CrossRefGoogle Scholar
  38. 38.
    Zhang, H., Y. Caudle, A. Shaikh, B. Yao, and D. Yin. 2018. Inhibition of microRNA-23b prevents polymicrobial sepsis-induced cardiac dysfunction by modulating TGIF1 and PTEN. Biomedicine & Pharmacotherapy 103: 869–878.CrossRefGoogle Scholar
  39. 39.
    Court, O., A. Kumar, J.E. Parrillo, and A. Kumar. 2002. Clinical review: Myocardial depression in sepsis and septic shock. Critical Care 6 (6): 500–508.CrossRefGoogle Scholar
  40. 40.
    Chagnon, F., C.N. Metz, R. Bucala, and O. Lesur. 2005. Endotoxin-induced myocardial dysfunction: effects of macrophage migration inhibitory factor neutralization. Circulation Research 96 (10): 1095–1102.CrossRefGoogle Scholar
  41. 41.
    Alves-Filho, J.C., A. de Freitas, F. Spiller, F.O. Souto, and C.Q. Cunha. 2008. The role of neutrophils in severe sepsis. Shock 30: 3–9.CrossRefGoogle Scholar
  42. 42.
    Cavaillon, J.M., and M. Adib-Conquy. 2005. Monocytes/macrophages and sepsis. Critical Care Medicine 33: S506–S509.CrossRefGoogle Scholar
  43. 43.
    O’Neill, L.A., F.J. Sheedy, and C.E. McCoy. 2011. MicroRNAs: the fine-tuners of Toll-like receptor signalling. Nature Reviews. Immunology 11 (3): 163–175.CrossRefGoogle Scholar
  44. 44.
    Williams, D.L., T. Ha, C. Li, J.H. Kalbfleisch, J. Schweitzer, W. Vogt, and I.W. Browder. 2003. Modulation of tissue Toll-like receptor 2 and 4 during the early phases of polymicrobial sepsis correlates with mortality. Critical Care Medicine 31 (6): 1808–1818.CrossRefGoogle Scholar
  45. 45.
    Gao, M., X. Wang, X. Zhang, T. Ha, H. Ma, L. Liu, J.H. Kalbfleisch, X. Gao, R.L. Kao, D.L. Williams, and C. Li. 2015. Attenuation of cardiac dysfunction in polymicrobial sepsis by microRNA-146a is mediated via targeting of IRAK1 and TRAF6 expression. Journal of Immunology 195 (2): 672–682.CrossRefGoogle Scholar
  46. 46.
    Ha, T., C. Lu, L. Liu, F. Hua, Y. Hu, J. Kelley, K. Singh, R.L. Kao, J. Kalbfleisch, D.L. Williams, X. Gao, and C. Li. 2010. TLR2 ligands attenuate cardiac dysfunction in polymicrobial sepsis via a phosphoinositide 3-kinase-dependent mechanism. American Journal of Physiology. Heart and Circulatory Physiology 298 (3): H984–H991.CrossRefGoogle Scholar
  47. 47.
    Medzhitov, R., P. Preston-Hurlburt, and C.A.J. Janeway. 1997. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388 (6640): 394–397.CrossRefGoogle Scholar
  48. 48.
    Nevière, R., H. Fauvel, C. Chopin, P. Formstecher, and P. Marchetti. 2001. Caspase inhibition prevents cardiac dysfunction and heart apoptosis in a rat model of sepsis. American Journal of Respiratory and Critical Care Medicine 163 (1): 218–225.CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Emergency MedicineTianjin Medical University General HospitalTianjinChina
  2. 2.Department of Internal MedicineThe University of Iowa Carver College of MedicineIowa CityUSA
  3. 3.Department of Critical Care MedicineTianjin Third Central HospitalTianjinChina

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