Endotoxemia-suppress cardiac function through dysregulation of mitochondrial biogenesis in mice model



Sepsis exaggerated proinflammatory response to infection that can progress to carries a significant cardiac dysfunction associated with morbidity and mortality. Mitochondrial biogenesis is involved in the control of cell metabolism, signal transduction, and regulation of mitochondrial reactive oxygen species (ROS) production. We are hypothesis that impairment of biogenesis has been invoked in the pathogenesis of myocardial endotoxemia. C57/BL6 mice were treated with LPS (0.5 mg/kg, iv) for 4 hrs. cardiac function was assessed using a microcatheter. Electronmicroscopy and confocal microscopy revealed that mitochondrial biogenesis is reduced after treatment the mice with LPS compared with control. Further, endotoxemic mice exhibited worse LV function than the control. The exaggerated cardiac contractile depression in LPS treated mice is associated with greater densities of neutrophils and mononuclear cells in the myocardium, and higher levels of TNF-α, IL-1β and IL-6 in the circulation and myocardium. This study will provide insights into mitochondrial biology, the relevance to sepsis, and therapeutic opportunities that possibly emerge.

Keywords: Sepsis; LPS; Proinflammatory response; Cardiac dysfunction; Biogenesis

Copyright © 2014 by The American Society for BioMedicine and BM-Publisher, Inc.

Article citationReferencesFull-Text/PDFBecome reviewer
The citation data is computed by the following citation measuring services:

Google scholarcitedby


  1. Muller-Decker K, Manegold G, Butz H, et al. Inhibition of cell proliferation by bacterial lipopolysaccharides in TLR4-positive epithelial cells: independence of nitric oxide and cytokine release. J Invest Dermatol. 2005;124:553–561. [PubMed]
  2. Tobias PS, Soldau K, Gegner JA, Mintz D, Ulevitch RJ. Lipopolysaccharide binding protein-mediated complexation of lipopolysaccharide with soluble CD14. J Biol Chem. 1995; 270:10482–10488. [PubMed]
  3. Hood DA, Takahashi M, Connor MK., Freyssenet D. Assembly of the cellular powerhouse: current issues in muscle mitochondrial biogenesis.  Exercise and Sport Sciences Reviews 2000; 28(2): 68–73, 2000. View at Scopus
  4. Abraham WT, Gilbert EM, Lowes BD, et al. Coordinate changes in Myosin heavy chain isoform gene expression are selectively associated with alterations in dilated cardiomyopathy phenotype. Molecular Medicine Cambridge, Mass. 2002; 8:750–760. [PubMed]
  5. Molkentin JD, Kalvakolanu DV, Markham BE. Transcription factor GATA-4 regulates cardiac muscle-specific expression of the alpha-myosin heavy-chain gene. Mol. Cell. Biol 1994;14: 4947–4957. [PubMed]
  6. Piantadosi CA, Suliman HB. Mitochondrial transcription factor A induction by redox activation of nuclear respiratory factor 1. J. Biol. Chem 2006; 281: 24–333. [PubMed]
  7. Laurie K. Russella, Brian N. Fincka, Daniel P. Kelly. Mouse models of mitochondrial dysfunction and heart failure. Journal of Molecular and Cellular Cardiology 2005; 38(1): 81-91. View at Publisher
  8. Crouser ED. Mitochondrial dysfunction in septic shock and multiple organ dysfunction syndrome. Mitochondrion. 2004; 4: 729–741. [PubMed]
  9. Huttemann M, Lee I, Samavati L, Yu H, Doan JW: Regulation of mitochondrial oxidative phosphorylation through cell signalingBiochim Biophys Acta 2007; 1773:1701-1720. [PubMed]
  10. Zapelini PH, Rezin GT, Cardoso MR, Ritter C, Klamt F, Moreira JC, et al.: Antioxidant treatment reverses mitochondrial dysfunction in a sepsis animal model. Mitochondrion 2008; 8: 211-218. [PubMed]
  11. Yousif NG. Fibronectin promotes migration and invasion of ovarian cancer cells through up‐regulation of FAK–PI3K/Akt pathway. Cell biology international 2014; 38 (1): 5-91. [PubMed]
  12. Hanada T, Yoshimura A. Regulation of cytokine signaling and inflammation. Cytokine Growth Factor Rev 2002; 13: 413-421. [PubMed]
  13. Orrenius S, Gogvadze A, Zhivotovsky B: Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol 2007; 47:143-183. [PubMed]
  14. Echtay KS, Murphy MP, Smith RA.J. Talbot DA, Brand MD. Superoxide activates mitochondrial uncoupling protein 2 from the matrix side. J. Biol. Chem 2002; 77: 47129–47135. Abstract/FREE Full Text
  15. Lin TK, Liou CW. Chen SD.  et al., Mitochondrial dysfunction and biogenesis in the pathogenesis of Parkinson's disease. Chang Gung Medical Journal 2009; 32(6); 589–599. View at Scopus
  16. Hock MB, Kralli A. Transcriptional control of mitochondrial biogenesis and function. Annual Review of Physiology 2009; 71: 177–203. View at Publisher · View at Google Scholar · View at Scopus
  17. Lagouge M, Argmann C, Gerhart-Hines Z. et al., Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 2006; 127( 6): 1109–1122. View at Publisher · View at Google Scholar · View at Scopus
  18. Suliman HB, Carraway MS, Ali AS, Reynolds CM, Welty-Wolf KE, Piantadosi CA. The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy. Journal of Clinical Investigation 2007; 117(12): 3730–3741. View at Publisher
  19. Nakai A, Yamaguchi O, Takeda T, et al. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med 2007; 13: 619–624. CrossRefMedline
  20. Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 2004; 6: 463–477. CrossRefMedline
  21. Shimomura H, Terasaki F, Hayashi T, Kitaura Y, Isomura T, Suma H. Autophagic degeneration as a possible mechanism of myocardial cell death in dilated cardiomyopathy. Jpn Circ J. 2001; 65: 965–968. CrossRefMedline
  22. Valentim L, Laurence KM, Townsend PA, et al. Urocortin inhibits Beclin1-mediated autophagic cell death in cardiac myocytes exposed to ischaemia/reperfusion injury. J Mol Cell Cardiol 2006; 40: 846–852.CrossRefMedline
  23.  Austin EW, Yousif NG, Ao L, Cleveland JC, Fullerton DA, Meng X. Ghrelin reduces myocardial injury following global ischemia and reperfusion via suppression of myocardial inflammatory response. AJBM 2013; 1(2): 38-48. View at Publisher
  24. Klionsky DJ, Abeliovich H, Agostinis P, et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 2008; 4: 151–175. Medline
  25. Brocheriou V, Hagege AA, Oubenaissa A, Cardiac functional improvement by a human Bcl-2 transgene in a mouse model of ischemia/reperfusion injury. J Gene Med 2000; 2: 326–333. CrossRefMedline
  26. Munusamy S, MacMillan-Crow LA. Mitochondrial superoxide plays a crucial role in the development of mitochondrial dysfunctionduring high glucose exposure in rat renal proximal tubular cells Free Radic. Biol. Med 2009; 46:1149–1157 Article View Record in Scopus
  27. Ventura-Clapier R, Garnier A, Veksler V.  Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha Cardiovasc. Res 2008; 79: 208–217 | Full Text via CrossRef
  28. Yousif NG, Al-amran FG. Novel Toll-like receptor-4 deficiency attenuates trastuzumab (Herceptin) induced cardiac injury in mice. BMC cardiovascular disorders 2011;11(1): 62. [PubMed]

Who Can Become a Reviewer?
Any expert in the article's research field can become a reviewer with American Journal of Biomedicine. Editors might ask you to look at a specific aspect of an article,...

Find out more

Review Article
DOI: http://dx.doi.org/10.18081/2333-5106/014-04/277-287
American Journal of BioMedicine 2014, Volume 2, Issue 4, pages 277-287
Received 04 June 2014; accepted October 07, 2014, Published November 30, 2014

How to cite this article
Bracale MM, Wonderge RB, Zhou M, Hazen EG. Endotoxemia-suppress cardiac function through dysregulation of mitochondrial biogenesis in mice model. American Journal of BioMedicine 2014;2(4):277-287

Case report outline
1. Abstract
2. Keywords
3. Introduction
4. Methods
5. Results
6. Discussion
7. References

Article metric