IRAK1 deletion disrupts cardiac Toll/IL-1 signaling and protects against contractile dysfunction
| Autor: | Jureta W. Horton, Debora D. Bryant, D. Jean White, James A. Thomas, Brett P. Giroir, May F. Tsen, Donna Frances Kusewitt, Sandra B. Haudek, Tolga F Koroglu |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Lipopolysaccharides
Male medicine.medical_specialty Physiology Ischemia Inflammation Receptors Cell Surface Biology Contractility Mice Physiology (medical) Internal medicine medicine Animals Heart Failure Mice Knockout Membrane Glycoproteins Septic shock Tumor Necrosis Factor-alpha Toll-Like Receptors IRAK1 medicine.disease Myocardial Contraction Mice Inbred C57BL Survival Rate Myocarditis Endocrinology Interleukin-1 Receptor-Associated Kinases Heart failure Circulatory system Acute Disease Chronic Disease Female medicine.symptom Signal transduction Cardiology and Cardiovascular Medicine Protein Kinases Interleukin-1 Signal Transduction |
| Zdroj: | American journal of physiology. Heart and circulatory physiology. 285(2) |
| ISSN: | 0363-6135 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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