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Published on: April 16, 2018
Melatonin protects against heart ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore
Giuseppe Petrosillo1, Giuseppe Colantuono, Nicola Moro
1Department of Biochemistry and Molecular Biology and CNR Institute of Biomembranes and Bioenergetics, Section of Anaesthesia, University of Bari, Bari, Italy.
Abstract:
Melatonin, a well-known antioxidant, has been shown to protect against ischemia-reperfusion myocardial damage. Mitochondrial permeability transition pore (MPTP) opening is an important event in cardiomyocyte cell death occurring during ischemia-reperfusion and therefore a possible target for cardioprotection. In the present study, we tested the hypothesis that melatonin could protect heart against ischemia-reperfusion injury by inhibiting MPTP opening. Isolated perfused rat hearts were subjected to global ischemia and reperfusion in the presence or absence of melatonin in a Langerdoff apparatus. Melatonin treatment significantly improves the functional recovery of Langerdoff hearts on reperfusion, reduces the infarct size, and decreases necrotic damage as shown by the reduced release of lactate dehydrogenase. Mitochondria isolated from melatonin-treated hearts are less sensitive than mitochondria from reperfused hearts to MPTP opening as demonstrated by their higher resistance to Ca(2+). Similar results were obtained following treatment of ischemic-reperfused rat heart with cyclosporine A, a known inhibitor of MPTP opening. In addition, melatonin prevents mitochondrial NAD(+) release and mitochondrial cytochrome c release and, as previously shown, cardiolipin oxidation associated with ischemia-reperfusion. Together, these results demonstrate that melatonin protects heart from reperfusion injury by inhibiting MPTP opening, probably via prevention of cardiolipin peroxidation.
Insights
Melatonin protects the heart from reperfusion injury by inhibiting mitochondrial permeability transition pore (MPTP) opening. This antioxidant effect reduces heart damage and improves functional recovery after ischemia.
Area of Science:
- Cardiovascular Science
- Mitochondrial Biology
- Pharmacology
Background:
- Ischemia-reperfusion injury significantly damages the heart.
- Mitochondrial permeability transition pore (MPTP) opening is a key factor in cardiomyocyte death during this injury.
- Targeting MPTP opening offers a potential cardioprotective strategy.
Purpose of the Study:
- To investigate if melatonin protects the heart against ischemia-reperfusion injury.
- To determine if melatonin's protective effect is mediated by inhibiting MPTP opening.
Main Methods:
- Isolated perfused rat hearts were subjected to global ischemia and reperfusion.
- Hearts were treated with melatonin or cyclosporine A (a known MPTP inhibitor).
- Functional recovery, infarct size, and mitochondrial sensitivity to MPTP opening were assessed.
Main Results:
- Melatonin treatment significantly improved heart function and reduced infarct size.
- Melatonin-treated hearts showed reduced release of lactate dehydrogenase, indicating less necrotic damage.
- Mitochondria from melatonin-treated hearts were more resistant to MPTP opening.
- Melatonin prevented mitochondrial release of NAD(+) and cytochrome c, and cardiolipin oxidation.
Conclusions:
- Melatonin confers cardioprotection against ischemia-reperfusion injury.
- This protection is achieved by inhibiting MPTP opening.
- Melatonin likely prevents MPTP opening by inhibiting cardiolipin peroxidation.
