IBIMOL   23987
INSTITUTO DE BIOQUIMICA Y MEDICINA MOLECULAR PROFESOR ALBERTO BOVERIS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Platelet serotonin aggravates myocardial reperfusion injury via degranulation
Autor/es:
HILGENDORF, INGO; AHRENS, INGO; STALLMANN, DIRK; MARCHINI, TIMOTEO; HERR, NADINE; BODE, CHRISTOPH; WOLF, DENNIS; KOENTGES, CHRISTOPH; WITSCH, THILO; MAULER, MAXIMILIAN; DUERSCHMIED, DANIEL; LEY, KLAUS; BUGGER, HEIKO; HAERDTNER, CARMEN; SCHOENICHEN, CATHLEEN
Lugar:
Barcelona
Reunión:
Congreso; European Society of Cardiology Congress 2017; 2017
Institución organizadora:
European Society of Cardiology
Resumen:
Background: Inflammation in the vascular compartment during reperfusion after acute myocardial infarction comes with a burst of neutrophils migrating into the heart. Serotonin (5-hydroxytryptamine; 5-HT; synthesized by tryptophan hydroxylase 1, TPH1) mediates neutrophil recruitment. Depletion of platelet serotonin attenuates this effect and leads to a protective phenotype upon inflammation.Purpose: Evaluation of serotonin mediated effects on acute phase inflammation during myocardial reperfusion injury.Methods: MI was induced in vivo for 30 minutes in C57Bl/6 (WT) and Tph1 deficient mice, followed by 24 hours of reperfusion. Heart function and infarct size was evaluated. Heart tissue was analyzed for cytokine expression and migrated inflammatory cells. Blood was taken to assess platelet neutrophil complexes as well as integrin and selectin expression on circulating neutrophils and platelets using flow cytometry.Ex vivo heart function was analyzed using the isolated working heart assay.Results: Plasma serotonin peaked 24 hours after in WT mice (150±10 ng/mL) and reached normal levels after 2 days (90±2 ng/mL). Heart function in Tph1−/− mice compared to WT after surgery was improved accompanied by a significant reduction of infarct size (35±3 in Tph1−/−; 53±5 in WT; % area at risk). This effect was absent in the ex vivo working heart mode. WT mice revealed increased MPO and TNFα expression within the heart and neutrophil content in the AAR was reduced in Tph1−/− mice (14±2 vs. 28±3 in WT per mm2 tissue) whereas monocytes were similar. Aortic root ICAM expression was similar in both groups (12±2 vs. 13±3% MFI) (Fig.1). Depletion of neutrophils by injection of an anti Ly6G antibody protected WT mice and reduced infarct size to 37±4%AAR.Looking at surface marker on neutrophils, we found a decreased expression of CD11b in Tph1−/− mice (30±5%) compared to WT mice (expression set 100%).In vitro analysis of neutrophils revealed that stimulation with 5-HT leads to increased surface CD11b and induces degranulation of neutrophils as indicated by electron microscopy.We could reproduce our in vitro findings in human neutrophils and also found a correlation of plasma 5-HT and neutrophil CD11b in ACS patients (r=0,846).Conclusion: Depletion of platelet serotonin greatly improves the outcome after I/R injury and leads to decreased infarct size and better heart function. This is contributed to an anti-inflammatory phenotype that comes with decreased neutrophil migration. We could identify neutrophils as a major contributor to myocardial reperfusion injury. Serotonin induces degranulation of neutrophils which results in increased CD11b expression on the cell surface. CD11b is one of the major mediators neutrophil adhesion to endothelial cells, which explains the pro-inflammatory properties caused by serotonin. Targeting serotonin-neutrophil interactions might open new strategies to control the inflammatory aspect of reperfusion injury.