Platelet activation is a major (patho‐) physiological mechanism that underlies ischemia/reperfusion (I/R) injury. In this study, we explored the molecular signals for platelet hyperactivity and investigated the beneficial effects of melatonin on platelet reactivity in response to I/R injury. After reperfusion, peroxisome proliferator‐activated receptor γ (PPARγ) was progressively downregulated in patients with acute myocardial infarction undergoing coronary artery bypass grafting (CABG) surgery and in mice with I/R injury model. Loss of PPARγ was closely associated with FUN14 domain containing 1 (FUNDC1) dephosphorylation and mitophagy activation, leading to increased mitochondrial electron transport chain complex (ETC.) activity, enhanced mitochondrial respiratory function, and elevated ATP production. The improved mitochondrial function strongly contributed to platelet aggregation, spreading, expression of P‐selectin, and final formation of micro‐thromboses, eventually resulting in myocardial dysfunction and microvascular structural destruction. However, melatonin powerfully suppressed platelet activation via restoration of the PPARγ content in platelets, which subsequently blocked FUNDC1‐required mitophagy, mitochondrial energy production, platelet hyperactivity, and cardiac I/R injury. In contrast, genetic ablation of PPARγ in platelet abolished the beneficial effects of melatonin on mitophagy, mitochondrial ATP supply, and platelet activation. Our results lay the foundation for the molecular mechanism of platelet activation in response to I/R injury and highlight that the manipulation of the PPARγ/FUNDC1/mitophagy pathway by melatonin could be a novel strategy for cardioprotection in the setting of cardiac I/R injury.

中文翻译：

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褪黑素通过PPARγ/ FUNDC1 /有丝分裂途径抑制血小板活化并抵抗心脏缺血/再灌注损伤

血小板激活是缺血/再灌注（I / R）损伤的主要（病理）生理机制。在这项研究中，我们探索了血小板功能亢进的分子信号，并研究了褪黑激素对响应I / R损伤的血小板反应性的有益作用。再灌注后，在接受冠状动脉旁路移植术（CABG）的急性心肌梗死患者和患有I / R损伤模型的小鼠中，过氧化物酶体增殖物激活受体γ（PPARγ）逐渐下调。PPARγ的丢失与包含1（FUNDC1）的FUN14域脱磷酸和线粒体活化密切相关，导致线粒体电子转运链复合物（ETC.）活性增加，线粒体呼吸功能增强和ATP产生增加。线粒体功能的改善极大地促进了血小板的聚集，扩散，P-选择素的表达以及最终形成的微血栓形成，最终导致了心肌功能障碍和微血管结构破坏。然而，褪黑激素通过恢复血小板中PPARγ的含量，有力地抑制了血小板的活化，从而阻止了FUNDC1所需的线粒体吞噬，线粒体能量产生，血小板活动亢进和心脏I / R损伤。相比之下，血小板中PPARγ的遗传消除消除了褪黑激素对线粒体，线粒体ATP供给和血小板活化的有益作用。