New strategies preventing ischemia/reperfusion damage through TLR4 antagonists
Title (trans.)
Nuevas estrategias para prevenir el daño por isquemia/reperfusión a través de antagonistas de TLR4Author
Paz García, MartaAdvisor
Boscá Gomar, LisardoEntity
UAM. Departamento de Bioquímica; Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM)Date
2021-02-02Subjects
Arterias coronarias - Enfermedades - Tesis dotorales; Reperfusión miocárdica -Terapias - Tesis doctorales; Biología y Biomedicina / BiologíaNote
Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 02-02-2021Esta tesis tiene embargado el acceso al texto completo hasta el 02-02-2027
Abstract
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
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