Mycophenolate Mofetil Attenuates Myocardial Ischemia-Reperfusion Injury via Regulation of the TLR4/NF-κB Signaling Pathway

Pharmazie. 2014 Nov;69(11):850-5.

Abstract

It has been well documented that the Toll-like receptor 4 (TLR4)/NF-κB signaling pathway mediates early inflammatory responses during myocardial ischemia and reperfusion (MI/R). Mycophenolate mofetil (MMF), an immunosuppressive agent, has been shown to confer protective effects against ischemia/reperfusion injury, possibly through its immunosuppressive and anti-inflammatory actions. The aim of the present study was to investigate whether MMF could modulate the TLR4/NF-κB signaling, inhibit cell apoptosis and subsequently attenuate MI/R injury. MMF (20 mg/kg) or vehicle was administered to SD rats by gavage. The rats were then subjected to MI/R injury. The results showed that after MI/R, the expressions of myocardial TLR4 and NF-κB were significantly increased, and apoptosis of cardiomyocytes was induced, as evidenced by the decreased mitochondrial membrane potential (MMP), decreased Bcl-2 protein level, and increased Bax expression. Administration of MMF attenuated MI/R injury. Further studies demonstrated that MMF inhibited the induction of TLR4, NF-κB and Bax expression, and restored the expression of bcl-2. Moreover, increased myeloperoxidase activity and serum level of tumor necrotic factor α induced by MI/R injury were also inhibited by MMF treatment. In conclusion, our results demonstrated that MMF attenuates MI/R injury through inhibition of the TLR4/NF-κB signaling pathway, which led to reduced inflammatory reaction and subsequently myocardial cell apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Heart / drug effects
  • Immunosuppressive Agents / therapeutic use*
  • Male
  • Membrane Potential, Mitochondrial / drug effects
  • Mycophenolic Acid / analogs & derivatives*
  • Mycophenolic Acid / therapeutic use
  • Myocardial Reperfusion Injury / drug therapy*
  • Myocytes, Cardiac / drug effects
  • NF-kappa B / drug effects*
  • Neutrophils / drug effects
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Toll-Like Receptor 4 / drug effects*
  • bcl-2-Associated X Protein / biosynthesis

Substances

  • Immunosuppressive Agents
  • NF-kappa B
  • Proto-Oncogene Proteins c-bcl-2
  • Toll-Like Receptor 4
  • bcl-2-Associated X Protein
  • Mycophenolic Acid