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Title

Beneficial effect of TLR4 blockade by a specific aptamer antagonist after acute myocardial infarction

AuthorsPaz-García, Marta CSIC; Povo-Retana, Adrián CSIC ORCID CVN; Jaén, Rafael I. CSIC ORCID; Prieto, Patricia CSIC ORCID; Peraza, Diego A. CSIC ORCID; Zaragoza, Carlos; Hernández-Jiménez, M.; Pineiro, David; Regadera, Javier; García-Bermejo, María Laura; Rodríguez-Serrano, Macarena; Sánchez-García, Sergio CSIC ORCID; Moro, María A.; Lizasoaín, Ignacio; Delgado, Carmen CSIC ORCID ; Valenzuela, Carmen CSIC ORCID CVN; Boscá, Lisardo CSIC ORCID CVN
KeywordsAptamer
TLR4
Myocardial infarction
Ischemia/reperfusion
Inflammation
ApTOLL
Issue DateFeb-2023
PublisherElsevier
CitationBiomedicine and Pharmacotherapy 158: 114214 (2023)
AbstractExperimental evidence indicates that the control of the inflammatory response after myocardial infarction is a key strategy to reduce cardiac injury. Cellular damage after blood flow restoration in the heart promotes sterile inflammation through the release of molecules that activate pattern recognition receptors, among which TLR4 is the most prominent. Transient regulation of TLR4 activity has been considered one of the potential therapeutic interventions with greater projection towards the clinic. In this regard, the characterization of an aptamer (4FT) that acts as a selective antagonist for human TLR4 has been investigated in isolated macrophages from different species and in a rat model of cardiac ischemia/reperfusion (I/R). The binding kinetics and biological responses of murine and human macrophages treated with 4FT show great affinity and significant inhibition of TLR4 signaling including the NF-κB pathway and the LPS-dependent increase in the plasma membrane currents (Kv currents). In the rat model of I/R, administration of 4FT following reoxygenation shows amelioration of cardiac injury function and markers, a process that is significantly enhanced when the second dose of 4FT is administered 24 h after reperfusion of the heart. Parameters such as cardiac injury biomarkers, infiltration of circulating inflammatory cells, and the expression of genes associated with the inflammatory onset are significantly reduced. In addition, the expression of anti-inflammatory genes, such as IL-10, and pro-resolution molecules, such as resolvin D1 are enhanced after 4FT administration. These results indicate that targeting TLR4 with 4FT offers new therapeutic opportunities to prevent cardiac dysfunction after infarction.
Publisher version (URL)http://dx.doi.org/10.1016/j.biopha.2023.114214
URIhttp://hdl.handle.net/10261/340250
DOI10.1016/j.biopha.2023.114214
ISSN0753-3322
Appears in Collections:(IIBM) Artículos




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