Pharmacological postconditioning effect of muramyl dipeptide is mediated through RIP2 and TAK1.
OBJECTIVE
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 ischaemia-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-beta-activated kinase-1 (TAK1). However, little is known about the RIP2/TAK1 pathway in the heart. The aim of this study was to determine whether the RIP2/TAK1 pathway has a cardioprotective role in a mouse model of myocardial infarction.


RESULTS
We isolated and subjected wild-type (WT) and RIP2(-/-) mouse hearts to 30 min of global ischaemia and 120 min of reperfusion with or without perfusion of MDP (10 microg/mL) before or after the ischaemic period and determined the infarct size. We examined activation of the TAK1/nuclear factor kappaB (NFkappaB) signalling pathway. The effect of TAK1 inhibition on MDP-induced cardioprotection was also evaluated. 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 NFkappaB activation via phosphorylation and degradation of IkappaB in the WT, but not in the RIP2(-/-), myocardium.


CONCLUSIONS
These results indicate that MDP at reperfusion induced cardioprotection through an RIP2/TAK1-dependent mechanism.
Sicard
Pierre
P
King's College London British Heart Foundation Centre of Research Excellence, The Cardiovascular Division, The Rayne Institute, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK.
Jacquet
Sebastien
S
Kobayashi
Koichi S
KS
Flavell
Richard A
RA
Marber
Michael S
MS
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D020672:I-kappa B Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010477:Perfusion; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects; D000099151:MAP Kinase Kinase Kinase 7
D000119:Acetylmuramyl-Alanyl-Isoglutamine; D002316:Cardiotonic Agents; D020672:I-kappa B Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D000099151:MAP Kinase Kinase Kinase 7; C506255:Ripk2 protein, mouse