TY - JOUR
T1 - Neutrophil stunning by metoprolol reduces infarct size
AU - García-Prieto, Jaime
AU - Villena-Gutiérrez, Rocío
AU - Gómez, Mónica
AU - Bernardo, Esther
AU - Pun-García, Andrés
AU - García-Lunar, Inés
AU - Crainiciuc, Georgiana
AU - Fernández-Jiménez, Rodrigo
AU - Sreeramkumar, Vinatha
AU - Bourio-Martínez, Rafael
AU - García-Ruiz, José M.
AU - Del Valle, Alfonso Serrano
AU - Sanz-Rosa, David
AU - Pizarro, Gonzalo
AU - Fernández-Ortiz, Antonio
AU - Hidalgo, Andrés
AU - Fuster, Valentín
AU - Ibanez, Borja
N1 - Publisher Copyright:
© The Author(s) 2017.
PY - 2017/4/18
Y1 - 2017/4/18
N2 - The β1-adrenergic-receptor (ADRB1) antagonist metoprolol reduces infarct size in acute myocardial infarction (AMI) patients. The prevailing view has been that metoprolol acts mainly on cardiomyocytes. Here, we demonstrate that metoprolol reduces reperfusion injury by targeting the haematopoietic compartment. Metoprolol inhibits neutrophil migration in an ADRB1-dependent manner. Metoprolol acts during early phases of neutrophil recruitment by impairing structural and functional rearrangements needed for productive engagement of circulating platelets, resulting in erratic intravascular dynamics and blunted inflammation. Depletion of neutrophils, ablation of Adrb1 in haematopoietic cells, or blockade of PSGL-1, the receptor involved in neutrophil-platelet interactions, fully abrogated metoprolol's infarct-limiting effects. The association between neutrophil count and microvascular obstruction is abolished in metoprolol-treated AMI patients. Metoprolol inhibits neutrophil-platelet interactions in AMI patients by targeting neutrophils. Identification of the relevant role of ADRB1 in haematopoietic cells during acute injury and the protective role upon its modulation offers potential for developing new therapeutic strategies.
AB - The β1-adrenergic-receptor (ADRB1) antagonist metoprolol reduces infarct size in acute myocardial infarction (AMI) patients. The prevailing view has been that metoprolol acts mainly on cardiomyocytes. Here, we demonstrate that metoprolol reduces reperfusion injury by targeting the haematopoietic compartment. Metoprolol inhibits neutrophil migration in an ADRB1-dependent manner. Metoprolol acts during early phases of neutrophil recruitment by impairing structural and functional rearrangements needed for productive engagement of circulating platelets, resulting in erratic intravascular dynamics and blunted inflammation. Depletion of neutrophils, ablation of Adrb1 in haematopoietic cells, or blockade of PSGL-1, the receptor involved in neutrophil-platelet interactions, fully abrogated metoprolol's infarct-limiting effects. The association between neutrophil count and microvascular obstruction is abolished in metoprolol-treated AMI patients. Metoprolol inhibits neutrophil-platelet interactions in AMI patients by targeting neutrophils. Identification of the relevant role of ADRB1 in haematopoietic cells during acute injury and the protective role upon its modulation offers potential for developing new therapeutic strategies.
UR - http://www.scopus.com/inward/record.url?scp=85017497647&partnerID=8YFLogxK
U2 - 10.1038/ncomms14780
DO - 10.1038/ncomms14780
M3 - Article
C2 - 28416795
AN - SCOPUS:85017497647
SN - 2041-1723
VL - 8
JO - Nature Communications
JF - Nature Communications
M1 - 14780
ER -