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Cardiovascular Research Advance Access [Accepted Manuscript] published online on February 12, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp055
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Pharmacological postconditioning effect of muramyl dipeptide is mediated through RIP2 and TAK1

Pierre Sicard1,*, Sebastien Jacquet1,*, Koichi S. Kobayashi2, Richard A. Flavell3 and Michael S. Marber1

1 King's College London British Heart Foundation Centre of Research Excellence, The Cardiovascular Division, The Rayne Institute, St. Thomas' Hospital, London SE1 7EH, United Kingdom
2 Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115
3 Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520

Corresponding author: Dr. Sebastien Jacquet, Department of Cardiology, King's College London, The Rayne Institute, St. Thomas' Hospital, Lambeth Palace Rd, London SE1 7EH, United Kingdom. E-mail: sebastien.jacquet{at}kcl.ac.uk

AIM: Despite their ability to cause septic shock and myocardial dysfunction, components of Gram-negative bacterial cell walls, like lipopolysaccharide, have been shown in numerous studies to induce myocardial protection during ischemia-reperfusion injury. Muramyl dipeptide (MDP) is another such component recognized by an intracellular receptor, nucleotide-binding oligomerization domain 2. Receptor activation leads to intracellular signals through receptor interacting protein-2 (RIP2) and tumour growth factor-β-activated kinase-1 (TAK1). However, little is known about the RIP2/TAK1 pathway in the heart. The aim of this study was to determine if the RIP2/TAK1 pathway has a cardioprotective role in a mouse model of myocardial infarction.

METHODS: We isolated and subjected wild-type (WT) and RIP2–/– mouse hearts to 30 minutes of global ischemia and 120 minutes of reperfusion with or without perfusion of MDP (10 µg/ml) before or after the ischemic period and determined the infarct size. We examined activation of the TAK1/nuclear factor {kappa}B (NF{kappa}B) signalling pathway. The effect of TAK1 inhibition on MDP-induced cardioprotection was also evaluated.

RESULTS: Exposure to MDP during reperfusion significantly reduced infarct size in WT hearts (from 51.7± 5.6% in control to 38.1± 6.7%, P < 0.05), but not in RIP2–/– hearts or in WT hearts with coincident pharmacological inhibition of TAK1. MDP treatment significantly increased the levels of p-TAK1 and p-JNK (Jun N-terminal kinase) and led to NF{kappa}B activation via phosphorylation and degradation of IkB in the WT, but not in the RIP2–/–, myocardium.

CONCLUSION: These results indicate that MDP at reperfusion induced cardioprotection through a RIP2/TAK1-dependent mechanism.

Time for primary review: 13 Days

* These authors contributed equally to this work.


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