Petrosillo Giuseppe, Colantuono Giuseppe, Moro Nicola, Ruggiero Francesca M, Tiravanti Edy, Di Venosa Nicola, Fiore Tommaso, Paradies Giuseppe
Department of Biochemistry and Molecular Biology and CNR Institute of Biomembranes and Bioenergetics, Section of Anaesthesia, University of Bari, Bari, Italy.
Am J Physiol Heart Circ Physiol. 2009 Oct;297(4):H1487-93. doi: 10.1152/ajpheart.00163.2009. Epub 2009 Aug 14.
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.
褪黑素是一种著名的抗氧化剂，已被证明可预防缺血再灌注引起的心肌损伤。线粒体通透性转换孔（MPTP）开放是缺血再灌注期间心肌细胞死亡的一个重要事件，因此可能是心脏保护的一个靶点。在本研究中，我们检验了褪黑素可通过抑制MPTP开放来保护心脏免受缺血再灌注损伤这一假说。在Langendorff装置中，将离体灌注的大鼠心脏在有或没有褪黑素的情况下进行全心缺血和再灌注。褪黑素处理显著改善了再灌注时Langendorff心脏的功能恢复，减小了梗死面积，并减少了坏死损伤，乳酸脱氢酶释放减少表明了这一点。从用褪黑素处理过的心脏分离出的线粒体比再灌注心脏的线粒体对MPTP开放的敏感性更低，这表现为它们对Ca(2+)的更高抗性。用环孢素A（一种已知的MPTP开放抑制剂）处理缺血再灌注的大鼠心脏后也获得了类似结果。此外，褪黑素可防止线粒体NAD(+)释放和线粒体细胞色素c释放，并且如先前所示，可防止与缺血再灌注相关的心磷脂氧化。总之，这些结果表明，褪黑素可能通过防止心磷脂过氧化来抑制MPTP开放，从而保护心脏免受再灌注损伤。
