Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/8347
Role of beta-adrenergic modulation in myocardial ischemia/reperfusion injury. Mechanisms underlyning cardioprotection
Garcia-Prieto, Jaime CNIC
Ibanez, Borja CNIC
Date of defense
The 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.
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