Pharmacological postconditioning effect of muramyl dipeptide is mediated through RIP2 and TAK1.
Cardiovasc Res
; 83(2): 277-84, 2009 Jul 15.
Article
em En
| MEDLINE
| ID: mdl-19213760
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 ANDRESULTS:
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Cardiotônicos
/
Traumatismo por Reperfusão Miocárdica
/
Acetilmuramil-Alanil-Isoglutamina
/
MAP Quinase Quinase Quinases
/
Proteína Serina-Treonina Quinases de Interação com Receptores
/
Infarto do Miocárdio
/
Miocárdio
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article