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

Abstract:

AIMS: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. METHODS AND 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. CONCLUSION:These results indicate that MDP at reperfusion induced cardioprotection through an RIP2/TAK1-dependent mechanism.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Sicard P,Jacquet S,Kobayashi KS,Flavell RA,Marber MS

doi

10.1093/cvr/cvp055

subject

Has Abstract

pub_date

2009-07-15 00:00:00

pages

277-84

issue

2

eissn

0008-6363

issn

1755-3245

pii

cvp055

journal_volume

83

pub_type

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