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

Authors

  • Zhongyi Chen,

    1. Cecile Cox Quillen Laboratory of Geriatric Research, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN
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  • Chu C. Chua,

    1. Cecile Cox Quillen Laboratory of Geriatric Research, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN
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  • Jinping Gao,

    1. Cecile Cox Quillen Laboratory of Geriatric Research, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN
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  • Kao-Wei Chua,

    1. Cecile Cox Quillen Laboratory of Geriatric Research, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN
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  • Ye-Shih Ho,

    1. Institute of Environmental Health Sciences and Department of Biochemistry and Molecular Biology, Wayne State University, Detroit, MI, USA
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  • Ronald C. Hamdy,

    1. Cecile Cox Quillen Laboratory of Geriatric Research, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN
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  • Balvin H. L. Chua

    1. Cecile Cox Quillen Laboratory of Geriatric Research, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN
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Address reprint requests to Dr Balvin H.L. Chua, James H. Quillen College of Medicine, East Tennessee State University, Box 70432, Johnson City, TN 37614, USA.
E-mail: chua@etsu.edu

Abstract

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.

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