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

Abstract

AimsDespite 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-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 whether the RIP2/TAK1 pathway has a cardioprotective role in a mouse model of myocardial infarction.Methods and resultsWe 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 g/mL) before or after the ischaemic period and determined the infarct size. We examined activation of the TAK1/nuclear factor κB (NFκB) 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 NFκB activation via phosphorylation and degradation of IkappaB in the WT, but not in the RIP2-/-, myocardium. ConclusionThese results indicate that MDP at reperfusion induced cardioprotection through an RIP2/TAK1-dependent mechanism. © The Author 2009.