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

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 (Gpxl). 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 x heart rate) was exacerbated in mice deficient in Gpxl (51 ± 3% for Gpxl +/+ mice versus 31 ± 6% for Gpxl -/- mice, P < 0.05). Administration of melatonin for 30 min protected against I/R injury in both Gpxl +/+ mice (72 ± 4.8%) and Gpxl -/- 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 Gpxl -/- mice than in Gpxl +/+ mice (75 ± 9% versus 54 ± 6%, P < 0.05) and were reduced significantly in melatonin-treated mice (31 ± 3.7% Gpxl -/- mice and 33 ± 6.0% Gpxl +/+ 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 Gpxl.