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Melatonin suppresses platelet activation and function against cardiac ischemia/reperfusion injury via PPAR γ/ FUNDC 1/mitophagy pathways
Author(s) -
Zhou Hao,
Li Dandan,
Zhu Pingjun,
Hu Shunying,
Hu Nan,
Ma Sai,
Zhang Ying,
Han Tianwen,
Ren Jun,
Cao Feng,
Chen Yundai
Publication year - 2017
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12438
Subject(s) - mitophagy , melatonin , platelet activation , reperfusion injury , platelet , cardioprotection , mitochondrion , medicine , ischemia , chemistry , peroxisome proliferator activated receptor , endocrinology , pharmacology , microbiology and biotechnology , receptor , biology , biochemistry , apoptosis , autophagy
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 ( PPAR γ) 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 PPAR γ was closely associated with FUN 14 domain containing 1 ( FUNDC 1) 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 PPAR γ content in platelets, which subsequently blocked FUNDC 1‐required mitophagy, mitochondrial energy production, platelet hyperactivity, and cardiac I/R injury. In contrast, genetic ablation of PPAR γ 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 PPAR γ/ FUNDC 1/mitophagy pathway by melatonin could be a novel strategy for cardioprotection in the setting of cardiac I/R injury.