Description:
Background: Myocardial reperfusion injury leads to platelet neutrophil complex (PNCs) migration into cardiac tissue, which promotes post-infarction necrosis. Local serotonin levels are elevated during ischemia and platelet serotonin promotes recruitment of inflammatory cells. Tryptophan hydroxylase-1-deficient mice (Tph1-/-) lack peripheral serotonin and show attenuated inflammatory response. We evaluated PNC infiltration after myocardial ischemia reperfusion (I/R) in the absence of peripheral serotonin. Methods: C57Bl/6 (WT) and Tph1-/- mice underwent coronary artery ligation to induce myocardial infarction. Reperfusion was allowed after 30min, heart function determined by echocardiography after 24h. Hearts were excised to evaluate infarct size. PNC content was determined by flow cytometry and histology. The function of healthy WT and Tph1-/- hearts was analyzed in an ex vivo working heart model and compared to global flow/no flow/flow. Cardiomyocytes were isolated from healthy WT and Tph1-/- mice and their survival following different in vitro challenges was assessed over 48h. Results: Infarct size was 37±9% in Tph1-/- and 53±13% area at risk in WT mice (p<0.01). Fractional shortening in echocardiography was better in Tph1-/- mice (49±4% vs. 41±6%, p<0.05), whereas cardiac power after no flow in the ex vivo working heart assay was similar (33±4 vs. 31±3mW/gHW). Isolated cardiomyocytes of Tph1-/- and WT mice showed similar survival after 48h (11.5% vs. 8.8%). These data indicate that contractility and cardiomyocyte function were independent of serotonin in this setting. Histology displayed a reduced number of PNCs in Tph1-/- hearts (7±3) compared to WT (16±3/350μm2, p<0.01). This was confirmed by flow cytometry of homogenized heart tissue (4±2 vs. 13±1%leukocytes, p<0.05) and blood samples (24±8 vs. 41±15%leukocytes; p<0.05). Conclusion: Lack of peripheral, i.e. platelet serotonin did not influence the function of isolated hearts or cardiomyocytes in vitro. However, PNC formation and infiltration was reduced in the absence of serotonin, resulting in attenuated reperfusion injury in vivo. Serotonin appears to account for up to 30% of myocardial reperfusion injury by promoting PNC formation.