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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褪黑激素通过 PPARγ/FUNDC1/线粒体自噬途径抑制血小板活化和功能，对抗心脏缺血/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，我们探索了血小板过度活跃的分子信号，并研究了褪黑激素对血小板反应性 I/R 损伤的有益影响。再灌注后，接受冠状动脉旁路移植术 (CABG) 手术的急性心肌梗死患者和 I/R 损伤模型小鼠中，过氧化物酶体增殖物激活受体 γ (PPARγ) 逐渐下调。 PPARγ 的缺失与 FUN14 结构域包含 1 (FUNDC1) 去磷酸化和线粒体自噬激活密切相关，导致线粒体电子传递链复合物 (ETC.) 活性增加、线粒体呼吸功能增强和 ATP 产量增加。线粒体功能的改善强烈促进血小板聚集、扩散、P-选择素的表达以及微血栓的最终形成，最终导致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的 PPARγ 含量来强力抑制血小板活化，从而阻止 FUNDC1 所需的线粒体自噬、线粒体能量产生、血小板过度活跃和心脏 I/R 损伤。相比之下，血小板中 PPARγ 的基因消除消除了褪黑激素对线粒体自噬、线粒体 ATP 供应和血小板活化的有益作用。我们的结果为血小板活化响应 I/R 损伤的分子机制奠定了基础，并强调褪黑激素对 PPARγ/FUNDC1/线粒体自噬途径的操纵可能是心脏 I/R 损伤情况下心脏保护的新策略。