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

Pierre Sicard1, Sebastien Jacquet, Koichi S Kobayashi

  • 1King'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.

Cardiovascular Research
|February 14, 2009
PubMed
Abstract

Insights

Muramyl dipeptide (MDP) protects the heart from injury after ischemia and reperfusion. This cardioprotection occurs via the nucleotide-binding oligomerization domain 2 (NOD2) receptor and the RIP2/TAK1 pathway, highlighting a novel therapeutic target.

Area of Science:

  • Cardiovascular Research
  • Immunology
  • Molecular Biology

Background:

  • Gram-negative bacterial cell wall components, such as lipopolysaccharide, can paradoxically protect the heart during ischemia-reperfusion injury.
  • Muramyl dipeptide (MDP), a bacterial cell wall component, is recognized by nucleotide-binding oligomerization domain 2 (NOD2), initiating intracellular signaling via receptor interacting protein-2 (RIP2) and tumor necrosis factor receptor-associated factor family member-associated NF-κB activator (TAK1).
  • The role of the RIP2/TAK1 pathway in cardiac protection against ischemia-reperfusion injury remains largely unexplored.

Purpose of the Study:

  • To investigate the cardioprotective role of the RIP2/TAK1 signaling pathway in a mouse model of myocardial infarction.
  • To determine if MDP confers protection against ischemia-reperfusion injury via the RIP2/TAK1 pathway.

Main Methods:

  • Wild-type (WT) and RIP2(-/-) mouse hearts were subjected to global ischemia and reperfusion.
  • Hearts were treated with MDP before or after ischemia, with or without TAK1 inhibition.
  • Infarct size was measured, and the activation of the TAK1/NF-κB signaling pathway (including p-TAK1, p-JNK, and IκB degradation) was assessed.

Main Results:

  • MDP administration during reperfusion significantly reduced infarct size in WT mouse hearts.
  • This cardioprotective effect of MDP was abolished in RIP2(-/-) hearts and in WT hearts with pharmacological TAK1 inhibition.
  • MDP treatment increased the phosphorylation of TAK1 and JNK, leading to NF-κB activation through IκB degradation in WT myocardium, but not in RIP2(-/-) myocardium.

Conclusions:

  • Muramyl dipeptide (MDP) confers significant cardioprotection against ischemia-reperfusion injury.
  • This protective effect is mediated through a mechanism dependent on the RIP2/TAK1 signaling pathway.
  • The findings suggest that targeting the RIP2/TAK1 pathway could be a novel therapeutic strategy for myocardial infarction.

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