The TIR/BB-loop mimetic AS-1 protects the myocardium from ischaemia/reperfusion injury.

Abstract

AIMS:

Innate immune and inflammatory responses are involved in myocardial ischaemia/reperfusion (I/R) injury. The interleukin-1 receptor (IL-1R)-mediated, MyD88-dependent nuclear factor kappa B (NF-kappaB) activation pathway plays an important role in the induction of innate immunity and inflammation. However, the role of the IL-1R-MyD88 pathway in myocardial I/R injury has not been thoroughly investigated. We hypothesized that inhibition of the interaction of IL-1R with MyD88 will attenuate myocardial ischaemic injury through reducing inflammatory responses.

METHODS AND RESULTS:

Male C57BL/6 mice were subjected to myocardial ischaemia (45 min) followed by reperfusion (4 h). In the treatment group, after mice were subjected to ischaemia (45 min), the TIR/BB-loop mimetic (AS-1), which inhibits the interaction of IL-1R with MyD88, was administered immediately before reperfusion. Hearts were harvested and cellular proteins were isolated for immunoprecipitation and immunoblotting. AS-1 administration significantly decreased infarct size by 32.92% compared with the untreated I/R group. Ejection fraction and fractional shortening in AS-1-treated mice were also significantly increased by 18.0 and 25.6%, respectively, compared with the untreated I/R group. AS-1 administration significantly decreased the I/R-increased interaction between IL-1R and MyD88, attenuated the I/R-increased NF-kappaB binding activity, and reduced levels of inflammatory cytokines and adhesion molecules in the myocardium compared with the untreated I/R group. In addition, AS-1 administration significantly decreased myocardial myeloperoxidase activity by 23.6% and neutrophil infiltration in the myocardium compared with the untreated I/R group.

CONCLUSION:

The results demonstrated an important role for the IL-1R-mediated MyD88-dependent signalling pathway in myocardial I/R injury. The data suggest that modulation of the IL-1R/MyD88 interaction could be a strategy for reducing myocardial ischaemic injury.

• Authors: Zhijuan Cao, Yulong Hu, Wei Wu, Tuanzhu Ha, Jim Kelley, Chenliang Deng, Qi Chen, Chuanfu Li, Jinheng Li, Yuehua Li
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 84 Issue 3 Pg. 442-51 (Dec 01 2009) ISSN: 1755-3245 [Electronic] England
• PMID: 19586942 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• NF-kappa B
• Pyrrolidines
• Receptors, Interleukin-1
• hydrocinnamoyl-1-valyl pyrrolidine
• Valine

Topics

• Animals
• Cell Movement (drug effects)
• Cytokines (metabolism)
• Disease Models, Animal
• Male
• Mice
• Mice, Inbred C57BL
• Myeloid Differentiation Factor 88 (metabolism)
• Myocardial Reperfusion Injury (metabolism, prevention & control)
• Myocardium (metabolism, pathology)
• NF-kappa B (metabolism)
• Neutrophils (pathology)
• Pyrrolidines (pharmacology, therapeutic use)
• Receptors, Interleukin-1 (metabolism)
• Signal Transduction (drug effects, physiology)
• Valine (analogs & derivatives, pharmacology, therapeutic use)
• Ventricular Dysfunction, Left (metabolism, prevention & control)