Cardiovascular Research Advance Access [Accepted Manuscript] published online on July 8, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp234
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The TIR/BB-Loop Mimetic AS-1 Protects the Myocardium from Ischemia/Reperfusion Injury
1 Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University; Nanjing 210029, China
2 Departments of Surgery, East Tennessee State University, Johnson City, TN 37614-0575, USA
3 Departments of Internal Medicine, East Tennessee State University, Johnson City, TN 37614-0575, USA
4 Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education), College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha 410081, China
* Address correspondence and reprint requests to Yuehua Li, M.D., Ph.D. Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu Province, 210029, China Tel: 86-025-86862886 Fax: 86-025-86862888 E-mail: yhli{at}njmu.edu.cn
Aims: Innate immune and inflammatory responses are involved in myocardial ischemia/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 ischemic injury through reducing inflammatory responses.
Methods: Male C57BL/6 mice were subjected to myocardial ischemia (45 min) followed by reperfusion (4 hrs). In the treatment group, after mice were subjected to ischemia (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.
Results: 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 NFB 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.
Conclusions: The results demonstrated an important role for the IL-1R-mediated MyD88-dependent signaling pathway in myocardial I/R injury. The data suggests that modulation of the IL-1R/MyD88 interaction could be a strategy for reducing myocardial ischemic injury.
KEYWORDS IL-1R; MyD88-dependent signaling; I/R injury; inflammation
Time for primary review: 33 Days
# Co-Corresponding author: Dr. Jinheng Li takes responsibility for AS-1 synthesis. Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education), College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha 410081, China. E-mail: jhli{at}hunnu.edu.cn