Inhibition of Toll-like receptor 4 with eritoran attenuates myocardial ischemia-reperfusion injury.
BACKGROUND
We previously reported that the functional mutation of Toll-like receptor 4 (TLR4) in C3H/HeJ mice subjected to myocardial ischemia-reperfusion (MI/R) injury resulted in an attenuation of myocardial infarction size. To investigate the ligand-activating TLR4 during MI/R injury, we evaluated the effect of eritoran, a specific TLR4 antagonist, on MI/R injury, with the goal of defining better therapeutic options for MI/R injury.


RESULTS
C57BL/6 mice received eritoran (5 mg/kg) intravenously 10 minutes before 30 minutes of in situ of transient occlusion of the left anterior descending artery, followed by 120 minutes of reperfusion. Infarct size was measured using triphenyltetrazoliumchloride staining. A c-Jun NH(2)-terminal kinase (JNK) activation was determined by Western blotting, nuclear factor (NF)-kappaB activity was detected by gel-shift assay, and cytokine expression was measured by ribonuclease protection assay. Mice treated with eritoran developed significantly smaller infarcts when compared with mice treated with vehicle alone (21.0+/-6.4% versus 30.9+/-13.9%; P=0.041). Eritoran pretreatment resulted in a reduction in JNK phosphorylation (eritoran versus vehicle: 3.98+/-0.81 versus 7.01+/-2.21-fold increase; P=0.020), less nuclear NF-kappaB translocation (2.70+/-0.35 versus 7.75+/-0.60-fold increase; P=0.00007), and a decrease in cytokine expression (P<0.05).


CONCLUSIONS
We conclude that inhibition of TLR4 with eritoran in an in situ murine model significantly reduces MI/R injury and markers of an inflammatory response.
Shimamoto
Akira
A
Department of Thoracic & Cardiovascular Surgery, Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu, Mie 514-8507, Japan.
Chong
Albert J
AJ
Yada
Masaki
M
Shomura
Shin
S
Takayama
Hiroo
H
Fleisig
Ani J
AJ
Agnew
Matthew L
ML
Hampton
Craig R
CR
Rothnie
Christine L
CL
Spring
Denise J
DJ
Pohlman
Timothy H
TH
Shimpo
Hideto
H
Verrier
Edward D
ED
D000818:Animals; D015415:Biomarkers; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004187:Disaccharides / Q000494:pharmacology / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D007249:Inflammation; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009203:Myocardial Infarction / Q000150:complications / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013403:Sugar Phosphates / Q000494:pharmacology / Q000627:therapeutic use*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000502:physiology
D015415:Biomarkers; D016207:Cytokines; D004187:Disaccharides; D016328:NF-kappa B; D013403:Sugar Phosphates; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C512420:eritoran; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases