Prevention of ischemia/reperfusion‐induced cardiac apoptosis and injury by melatonin is independent of glutathione peroxdiase 1

Abstract:  Free‐radical generation is one of the primary causes of myocardial ischemia/reperfusion (I/R) injury. Melatonin is an efficient free‐radical scavenger and induces the expression of antioxidant enzymes. We have previously shown that melatonin can prevent free‐radical‐induced myocardial injury. To date, the mechanism underlying melatonin’s cardioprotective effect is not clear. In this study, we assessed the ability of melatonin to protect against I/R injury in mice deficient in glutathione peroxidase 1 (Gpx1). Mice hearts were subjected to 40 min of global ischemia in vitro followed by 45 min of reperfusion. Myocardial I/R injury (expressed as % of recovery of left ventricular developed pressure × heart rate) was exacerbated in mice deficient in Gpx1 (51 ± 3% for Gpx1+/+ mice versus 31 ± 6% for Gpx1−/− mice, P < 0.05). Administration of melatonin for 30 min protected against I/R injury in both Gpx1+/+ mice (72 ± 4.8%) and Gpx1−/− mice (63 ± 4.7%). This protection was accompanied by a significant improvement in left ventricular end‐diastolic pressure and a twofold decrease in lactate dehydrogenase (LDH) level released from melatonin‐treated hearts. In another set of experiments, mice were subjected to 50 min of ligation of the left descending anterior coronary artery in vivo followed by 4 hr of reperfusion. The infarct sizes, expressed as the percentage of the area at risk, were significantly larger in Gpx1−/− mice than in Gpx1+/+ mice (75 ± 9% versus 54 ± 6%, P < 0.05) and were reduced significantly in melatonin‐treated mice (31 ± 3.7% Gpx1−/− mice and 33 ± 6.0% Gpx1+/+ mice). In hearts subjected to 30 min of coronary artery occlusion followed by 3 hr of reperfusion, melatonin‐treated hearts had significantly fewer in situ oligo ligation‐positive myocytes and less protein nitration. Our results demonstrate that the cardioprotective function of melatonin is independent of Gpx1.