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Updated: Jul 26, 2026
A Simple and Efficient Method for In Vivo Cardiac-specific Gene Manipulation by Intramyocardial Injection in Mice
Published on: April 16, 2018
Melatonin suppresses platelet activation and function against cardiac ischemia/reperfusion injury via
Hao Zhou1,2, Dandan Li1, Pingjun Zhu1
1Department of Cardiology, Chinese PLA General Hospital, Beijing, China.
Abstract:
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.
Insights
Melatonin protects against ischemia/reperfusion (I/R) injury by restoring peroxisome proliferator-activated receptor γ (PPARγ) in platelets. This action inhibits mitochondrial dysfunction and platelet hyperactivity, crucial for reducing cardiac damage.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Medicine
- Platelet Physiology
Background:
- Platelet activation is central to ischemia/reperfusion (I/R) injury.
- Understanding the molecular triggers of platelet hyperactivity in I/R is critical for developing therapies.
Purpose of the Study:
- To elucidate molecular signals driving platelet hyperactivity during I/R.
- To investigate the protective effects of melatonin on platelet reactivity in I/R injury.
Main Methods:
- Analysis of peroxisome proliferator-activated receptor γ (PPARγ) levels in patients and mice with I/R injury.
- Investigating the role of FUND14 domain containing 1 (FUNDC1) and mitophagy in platelet activation.
- Assessing the impact of melatonin on platelet function and cardiac I/R injury.
- Utilizing genetic ablation of PPARγ to confirm its role.
Main Results:
- PPARγ was downregulated post-I/R, correlating with FUNDC1 dephosphorylation and mitophagy activation.
- Enhanced mitochondrial activity and ATP production in platelets contributed to thrombosis and cardiac dysfunction.
- Melatonin treatment restored PPARγ, suppressed mitophagy, reduced platelet hyperactivity, and alleviated cardiac I/R injury.
- PPARγ deficiency abolished melatonin's protective effects.
Conclusions:
- The PPARγ/FUNDC1/mitophagy pathway is a key mechanism in I/R-induced platelet activation.
- Melatonin demonstrates potential as a cardioprotective agent by modulating this pathway.
- Targeting PPARγ offers a novel therapeutic strategy for cardiac I/R injury.
