New strategies preventing ischemia/reperfusion damage through TLR4 antagonists

Zusammenfassung

Despite advances in the study of cardiovascular diseases, these remain the leading cause of death and morbidity in the world. Controlling the inflammatory component and trying to minimize cardiac dysfunction stands out as the most hopeful strategy. When signs of cellular damage are present, sterile inflammation is initiated by the activation of pattern recognition receptors (PRRs), among which toll-like receptor (TLR)-4 is the most studied. TLR4 is present in numerous cell types, mainly in monocytes and macrophages, and TLR4 is considered one of the therapeutic targets with greater projection towards the clinic. In this regard, aptamers are projected as a pharmacological tool with several advantages over immunotherapy regulating these receptors. The main objective was the study of the therapeutic potential of ApTLR#4FT, an aptamer designed as a specific and selective antagonist of human TLR4, in different animal models of cardiac pathology, specifically atherosclerosis and myocardial infarction (MI). Thus, first, the binding kinetics, functionality and toxicity of ApTLR#4FT to TLR4 in macrophages and cardiomyocytes of different species (human, simian, rat and mouse) were analyzed in vitro. On the one hand, in the in vivo study of ApTLR#4FT and ApTLR#4F for atherosclerosis a murine model was used. On the other hand, myocardial infarction analysis was studied with two different experimental models: permanent occlusion and ischemia/reperfusion (I/R). Data not shown due to confidentiality guidelines. In summary, this work presents an approximation using the aptamer ApTLR#4FT as a possible therapeutic alternative in the case of a complex pathology as MI. Additionally, regarding the results obtained, it seems appropriate to perform new studies to complete the characterization of the protective effect of the aptamer (including administration of several doses) in these animal models in order to prevent the phase of tissue damage after the I/R