Key result
Platelet serotonin depletion reduces myocardial infarct size by an absolute ~19% after reperfusion injury.
Why the study?
Platelets release stored serotonin during thrombus formation or acute inflammation to facilitate hemostasis and modulate inflammatory responses, but its role in myocardial reperfusion injury required investigation.
Absolute Event Rate: 36.4% vs 55.3%
Platelet-derived serotonin acts as a crucial driver of neutrophil degranulation and exacerbates myocardial reperfusion injury, suggesting that selective serotonin reuptake inhibitors could be repurposed to limit infarct size.
BACKGROUND: Platelets store large amounts of serotonin that they release during thrombus formation or acute inflammation. This facilitates hemostasis and modulates the inflammatory response. METHODS: Infarct size, heart function, and inflammatory cell composition were analyzed in mouse models of myocardial reperfusion injury with genetic and pharmacological depletion of platelet serotonin. These studies were complemented by in vitro serotonin stimulation assays of platelets and leukocytes in mice and men, and by measuring plasma serotonin levels and leukocyte activation in patients with acute coronary syndrome. RESULTS: ) and increased expression of membrane-bound leukocyte adhesion molecule CD11b, leading to enhanced inflammation in the infarct area and reduced myocardial salvage. In patients hospitalized with acute coronary syndrome, plasmatic serotonin levels correlated with CD11b expression on neutrophils and myeloperoxidase plasma levels. Long-term serotonin reuptake inhibition-reported to protect patients with depression from cardiovascular events-resulted in the depletion of platelet serotonin stores in mice. These mice displayed a reduction in neutrophil degranulation and preserved cardiac function. In line, patients with depression using serotonin reuptake inhibition, presented with suppressed levels of CD11b surface expression on neutrophils and lower myeloperoxidase levels in blood. CONCLUSIONS: Taken together, we identify serotonin as a potent therapeutic target in neutrophil-dependent thromboinflammation during myocardial reperfusion injury.
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Mauler et al. (2019) studied Myocardial ischemia/reperfusion injury. Platelet serotonin depletion (genetic Tph1-/- or pharmacological fluoxetine) vs. Wild-type mice or vehicle was evaluated on Infarct size (% area at risk). Depletion of platelet serotonin significantly reduced infarct size compared to wild-type controls (36.4% vs 55.3% area at risk) in a mouse model of myocardial reperfusion injury.
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