RGD Reference Report - IRAK1 deletion disrupts cardiac Toll/IL-1 signaling and protects against contractile dysfunction. - Rat Genome Database

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IRAK1 deletion disrupts cardiac Toll/IL-1 signaling and protects against contractile dysfunction.

Authors: Thomas, JA  Haudek, SB  Koroglu, T  Tsen, MF  Bryant, DD  White, DJ  Kusewitt, DF  Horton, JW  Giroir, BP 
Citation: Thomas JA, etal., Am J Physiol Heart Circ Physiol. 2003 Aug;285(2):H597-606.
RGD ID: 1582271
Pubmed: PMID:12860565   (View Abstract at PubMed)
DOI: DOI:10.1152/ajpheart.0655.2001   (Journal Full-text)

Myocardial contractile dysfunction accompanies both systemic and cardiac insults. Septic shock and burn trauma can lead to reversible contractile deficits, whereas 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/interleukin-1 (IL-1) signal transduction pathway. Interestingly, components of this pathway are also expressed in normal and failing hearts, although 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 after different insults were tested. Results from these experiments demonstrate that lipopolysaccharides (LPS) activate Toll/IL-1 signaling and 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
myocarditis  ISOIrak1 (Mus musculus)1582271; 1582271 RGD 
myocarditis  IMP 1582271 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Irak1  (interleukin-1 receptor-associated kinase 1)

Genes (Mus musculus)
Irak1  (interleukin-1 receptor-associated kinase 1)

Genes (Homo sapiens)
IRAK1  (interleukin 1 receptor associated kinase 1)

Objects referenced in this article
Gene MAP2K5 mitogen-activated protein kinase kinase 5 Homo sapiens
Gene Map2k5 mitogen-activated protein kinase kinase 5 Mus musculus
Gene Map2k5 mitogen activated protein kinase kinase 5 Rattus norvegicus

Additional Information