title: Melatonin protects against heart ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology and CNR Institute of Biomembranes and Bioenergetics, Section of Anaesthesia, University of Bari, Bari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Petrosillo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Colantuono
authors.forename: Nicola
authors.initials: N
authors.lastname: Moro
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Ruggiero
authors.forename: Edy
authors.initials: E
authors.lastname: Tiravanti
authors.forename: Nicola
authors.initials: N
authors.lastname: Di Venosa
authors.forename: Tommaso
authors.initials: T
authors.lastname: Fiore
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Paradies
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002308:Cardiolipins / Q000378:metabolism; D002317:Cardiovascular Agents / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009243:NAD / Q000378:metabolism; D009336:Necrosis; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D000975:Antioxidants; D002308:Cardiolipins; D002317:Cardiovascular Agents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009243:NAD; D016572:Cyclosporine; D045304:Cytochromes c; D007770:L-Lactate Dehydrogenase; D008550:Melatonin; D002118:Calcium