Cardiomyocyte Toll-like receptor 4 is involved in heart dysfunction following septic shock or myocardial ischemia

Reut Fallach, Asher Shainberg, Orna Avlas, Michael Fainblut, Yelena Chepurko, Eyal Porat, Edith Hochhauser

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128 Scopus citations


Toll-like receptors are expressed in immune cells and cardiac muscle. We examined whether the cardiac Toll-like receptor 4 (TLR4) is involved in the acute myocardial dysfunction caused by septic shock and myocardial ischemia (MI). We used wild type mice (WT), TLR4 deficient (TLR4-ko) mice and chimeras that underwent myeloablative bone marrow transplantation to dissociate between TLR4 expression in the heart (TLR4-ko/WT) and the immunohematopoietic system (WT/TLR4-ko). Mice were injected with lipopolysaccharide (LPS) (septic shock model) or subjected to coronary artery ligation (MI model) and tested in vivo and ex vivo, for function, histopathology proinflammatory cytokine and TLR4 expression. WT mice challenged with LPS or MI displayed reduced cardiac function, increased myocardial levels of IL-1β and TNF-α and upregulation of mRNA encoding TLR4 prior to myocardial leukocyte infiltration. TLR4 deficient mice sustained significantly smaller infarctions as compared to control mice at comparable areas at risk. The cardiac function of TLR4-ko mice was not affected by LPS and demonstrated reduced suppression by MI compared to WT. Chimeras deficient in myocardial TLR4 were resistant to suppression induced by LPS and the heart function was less depressed, compared to the TLR4-ko, following MI in the acute phase (4. h). In contrast, hearts of chimeras deficient in immunohematopoietic TLR4 expression were suppressed both by LPS and MI, exhibiting increased myocardial cytokine levels, similar to WT mice. We concluded that cardiac function of TLR4-ko mice and chimeric mice expressing TLR4 in the immunohematopoietic system, but not in the heart, revealed resistance to LPS and reduced cardiac depression following MI, suggesting that TLR4 expressed by the cardiomyocytes themselves plays a key role in this acute phenomenon.

Original languageEnglish
Pages (from-to)1236-1244
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Issue number6
StatePublished - Jun 2010

Bibliographical note

Funding Information:
This work was performed in partial fulfillment of the requirements for Reut Fallach's Ph.D. degree studied at the, Gonda (Goldschmied) Medical Diagnostic Research Center, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel and was partially supported by the Israel Ministry of Health .


  • Interleukin 1β
  • Lipopolysaccharide
  • Myocardial ischemia
  • Toll-like receptor 4
  • Tumor necrosis factor α


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