eritoran and Myocardial-Infarction

Toll-like receptors (TLRs) are a family of pattern recognition receptors involved in cardiovascular diseases. Notably, numerous studies have demonstrated that TLR4 activates the expression of several of pro-inflammatory cytokine genes that play pivotal roles in myocardial inflammation, particularly myocarditis, myocardial infarction, ischemia-reperfusion injury, and heart failure. In addition, TLR4 is an emerging target for anti-inflammatory therapies. Given the significance of TLR4, it would be useful to summarize the current literature on the molecular mechanisms and roles of TLR4 in myocardial inflammation. Thus, in this review, we first introduce the basic knowledge of the TLR4 gene and describe the activation and signaling pathways of TLR4 in myocardial inflammation. Moreover, we highlight the recent progress of research on the involvement of TLR4 in myocardial inflammation. The information reviewed here may be useful to further experimental research and to increase the potential of TLR4 as a therapeutic target.

Topics: Animals; Cardiotonic Agents; Clinical Trials as Topic; Disaccharides; Follistatin; Gene Expression Regulation; Heart Failure; Humans; Metformin; Myeloid Differentiation Factor 88; Myocardial Infarction; Myocarditis; Myocardium; NF-kappa B; Reperfusion Injury; Signal Transduction; Sugar Phosphates; Toll-Like Receptor 4

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.. 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).. 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.

Topics: Animals; Biomarkers; Cytokines; Disaccharides; Drug Evaluation, Preclinical; Enzyme Activation; Inflammation; JNK Mitogen-Activated Protein Kinases; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Myocardial Infarction; Myocardial Reperfusion Injury; NF-kappa B; Phosphorylation; Protein Processing, Post-Translational; Sugar Phosphates; Toll-Like Receptor 4