title: The TIR/BB-loop mimetic AS-1 protects the myocardium from ischaemia/reperfusion injury.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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: Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu Province 210029, China.
authors: Zhijuan
authors: Z
authors: Cao
authors: Yulong
authors: Y
authors: Hu
authors: Wei
authors: W
authors: Wu
authors: Tuanzhu
authors: T
authors: Ha
authors: Jim
authors: J
authors: Kelley
authors: Chenliang
authors: C
authors: Deng
authors: Qi
authors: Q
authors: Chen
authors: Chuanfu
authors: C
authors: Li
authors: Jinheng
authors: J
authors: Li
authors: Yuehua
authors: Y
authors: Li
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000473:pathology; D011759:Pyrrolidines / Q000494:pharmacology* / Q000627:therapeutic use*; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000517:prevention & control
chemical_list: D016207:Cytokines; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011759:Pyrrolidines; D017472:Receptors, Interleukin-1; C475931:hydrocinnamoyl-1-valyl pyrrolidine; D014633:Valine