Cardiovascular Research Advance Access first published online on July 8, 2009
This version [Corrected Proof] published online on July 31, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp234
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The TIR/BB-loop mimetic AS-1 protects the myocardium from ischaemia/reperfusion injury
1 Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu Province 210029, China
2 Department of Surgery, East Tennessee State University, Johnson City, TN 37614-0575, USA
3 Department of Internal Medicine, East Tennessee State University, Johnson City, TN 37614-0575, USA
4 Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research (Ministry of Education), College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha 410081, China
* Corresponding author. Tel: +86 25 8686 2886; fax: +86 25 8686 2888. E-mail address: yhli{at}njmu.edu.cn (Y.L.)/jhli{at}hunnu.edu.cn (J.L.)
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-
B) 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-B 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.
KEYWORDS IL-1R; MyD88-dependent signalling; I/R injury; Inflammation
Time for primary review: 33 days