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dc.contributor.advisorIbanez, Borja 
dc.contributor.authorGarcia-Prieto, Jaime 
dc.date.accessioned2019-09-13T13:46:20Z
dc.date.available2019-09-13T13:46:20Z
dc.date.issued2017-12-18
dc.identifier.urihttp://hdl.handle.net/20.500.12105/8347
dc.description.abstractThe β-adrenergic system plays an important role in the regulation of heart function. The early intravenous administration of ß1-adrenergic receptor (ADRB1)-antagonist, metoprolol, in patients with ST-segment elevation acute myocardial infarction (AMI) reduces the extent of infarct size. The prevailing view has been that metoprolol acts mainly on cardiomyocytes function, reducing cardiac output. This work presents evidence that metoprolol reduces ischemia/reperfusion injury by targeting the hematopoietic compartment, specifically by inhibiting neutrophil function through an ADRB1 signallingdependent manner. Metoprolol acts during early phases of neutrophil recruitment, impairing structural and functional rearrangements necessary for effective interactions with circulating platelets to occur. Metoprolol, “stuns” neutrophils that cannot engage the structural conformation necessary to infiltrate tissues, triggering erratic intravascular dynamics and overall blunted inflammation. The in vitro functional assays confirm direct effect on neutrophils through an ADRB1-dependent mechanism. The depletion of circulating neutrophils, the lack of the Adrb1 in hematopoietic cells and the blockade of P-selectin glycoprotein ligand-1, the receptor involved in neutrophil-platelet interactions, result in a complete abrogation of metoprolol´s infarct-limiting effect. Moreover, the association between neutrophil count and microvascular obstruction is abolished in early metoprolol-treated AMI patients. Metoprolol has no direct effect on platelet function, but inhibits neutrophil-platelet interactions in AMI patients by targeting neutrophils directly. Identification of the relevant role of ADRB1 in hematopoietic cells during acute injury and the protective role upon its modulation offers potential for developing new therapeutic strategies.es_ES
dc.description.sponsorshipThis work was supported by a competitive grant from the Spanish Ministry of Economy and Competitiveness (MINECO) through the Carlos III Institute of Health-Fondo de Investigación Sanitaria FIS-ISCIII (PI13/01979) and FISISCIII (PI10/02268), Fundacion Mutua Madrileña (AP8695-2011), from the competitive ‘‘CNIC translational 01/2009’’ and European Regional Development Fund (ERDF/FEDER) funds (PI10/02268 & PI13/01979). The CNIC is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505).es_ES
dc.language.isoenges_ES
dc.titleRole of beta-adrenergic modulation in myocardial ischemia/reperfusion injury. Mechanisms underlyning cardioprotectiones_ES
dc.typeTesis doctorales_ES
dc.identifier.doi10.4321/repisalud.8347
dc.contributor.funderMinisterio de Economía y Competitividad (España)es_ES
dc.contributor.funderInstituto de Salud Carlos III - ISCIIIes_ES
dc.contributor.funderFundación Mutua Madrileña Automovilísticaes_ES
dc.contributor.funderEuropean Regional Development Fund (ERDF/FEDER)es_ES
dc.contributor.funderFundación ProCNICes_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Laboratorio Traslacional para la Imagen y Terapia Cardiovasculares_ES
dc.repisalud.institucionCNICes_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses_ES


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