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1 Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
2 Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA
3 Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA
4 Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA
* To whom correspondence should be addressed. E-mail: James.Thomas{at}UTSouthwestern.edu.
Myocardial contractile dysfunction accompanies both systemic and cardiac insults. Septic shock and burn trauma can lead to reversible contractile deficits, while ischemia and direct inflammation of the heart can precipitate transient or permanent impairments in contractility. Many of the insults that trigger contractile dysfunction also activate the innate immune system. Activation of the innate immune response to infection is coordinated by the conserved Toll/IL-1 signal transduction pathway. Interestingly, components of this pathway are also expressed in normal and failing hearts, though their function is unknown. The hypotheses that Toll/IL-1 signaling occurs in the heart and that intact pathway function is required for contractile dysfunction following different insults were tested. Results from these experiments demonstrate that lipopolysaccharide (LPS) activates Toll/IL-1 signaling and the IL-1 receptor-associated kinase-1 (IRAK1), a critical pathway intermediate, in the heart, indicating that the function of this pathway is not limited to immune system tissues. Moreover, hearts lacking IRAK1 exhibit impaired LPS-triggered downstream signal transduction. Hearts from IRAK1-deficient mice also resist acute LPS-induced contractile dysfunction. Finally, IRAK1 inactivation enhances survival of transgenic mice that develop severe myocarditis and lethal heart failure. Thus, the Toll/IL-1 pathway is active in myocardial tissue and interference with pathway function, through IRAK1 inactivation, may represent a novel strategy to protect against cardiac contractile dysfunction.
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