Platelet Serotonin Aggravates Myocardial Ischemia/Reperfusion Injury via Neutrophil Degranulation
Platelet Serotonin Aggravates Myocardial Ischemia/Reperfusion Injury via Neutrophil Degranulation
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DOI：
10.1161/circulationaha.118.033942
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发表时间：
2019-02-12
期刊：
影响因子：
37.8
通讯作者：
Duerschmied, Daniel
中科院分区：
文献类型：
--
作者：
Mauler, Maximilian;Herr, Nadine;Duerschmied, Daniel
背景：血小板储存大量血清素，在血栓形成或急性炎症时释放。这有助于止血和调节炎症反应。方法：分析血小板5 -羟色胺遗传和药理学耗竭的心肌再灌注损伤小鼠模型的梗死面积、心功能和炎症细胞组成。这些研究还通过对小鼠和男性的血小板和白细胞进行体外血清素刺激试验，并通过测量急性冠状动脉综合征患者的血浆血清素水平和白细胞活化来补充。结果：血小板源性血清素诱导中性粒细胞脱粒，释放髓过氧化物酶和过氧化氢（H2O2），增加膜结合白细胞粘附分子CD11b的表达，导致梗死区炎症增强，心肌恢复减少。急性冠状动脉综合征住院患者血浆血清素水平与中性粒细胞CD11b表达和髓过氧化物酶血浆水平相关。长期的5 -羟色胺再摄取抑制——据报道可以保护抑郁症患者免受心血管事件的影响——导致小鼠血小板5 -羟色胺储存的消耗。这些小鼠表现出中性粒细胞脱颗粒减少和心功能保存。与此同时，使用5 -羟色胺再摄取抑制剂的抑郁症患者表现为中性粒细胞CD11b表面表达水平受到抑制，血液中髓过氧化物酶水平降低。结论：综上所述，我们确定血清素是心肌再灌注损伤期间中性粒细胞依赖性血栓炎症的有效治疗靶点。
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: Platelet-derived serotonin induced neutrophil degranulation with release of myeloperoxidase and hydrogen peroxide (H2O2) 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. Longterm 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.