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Cardiovascular Research 2002 55(2):309-319; doi:10.1016/S0008-6363(02)00412-1
© 2002 by European Society of Cardiology
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Copyright © 2002, European Society of Cardiology

Adenovirus-mediated expression of p35 prevents hypoxia/reoxygenation injury by reducing reactive oxygen species and caspase activity

Taro Date, Adam J Belanger, Seibu Mochizuki, Jennifer A Sullivan, Louis X Liu, Abraham Scaria, Seng H Cheng, Richard J Gregory and Canwen Jiang*

Genzyme Corporation, 31 New York Avenue, Framingham, MA 01701, USA

* Corresponding author. Tel.: +1-508-270-2418; fax: +1-508-872-4091 canwen.jiang{at}genzyme.com

Objective: This study aimed to examine the effects of adenovirus-mediated expression of p35, a baculovirus gene, on apoptosis induced by hypoxia/reoxygenation (H/R) in cardiomyocytes. Methods: Neonatal rat cardiomyocytes were infected with recombinant adenoviral vectors expressing p35 (Ad2/CMVp35) or no transgene (Ad2/CMVEV) and were then subjected to H/R. Separate groups of non-infected cardiomyocytes were treated with pharmacological caspase inhibitors or antioxidants. Cell viability, apoptosis, caspase activity, and cellular reactive oxygen species (ROS) were measured using various assays. Results: H/R decreased cell viability and increased cellular ROS levels, caspase activity, and cell apoptosis. Infection with Ad2/CMVp35 effectively inhibited the increase in cellular ROS levels, the activities of caspases 3 and 8, apoptosis, and cell death following H/R, whereas Ad2/CMVEV had no effect. Despite its ability to abolish the increase in caspase activity and partially inhibit apoptosis, the pan-caspase inhibitor ZVAD-fmk (100 µM) failed to significantly reduce cell death induced by H/R. N-acetyl-L-cysteine, an antioxidant, completely inhibited H/R-induced increase in cellular ROS levels, but reduced apoptosis and cell death by 30% only. Conclusions: Adenovirus-mediated expression of p35 effectively inhibits H/R-induced cardiomyocyte apoptosis by reducing cellular ROS levels and inhibiting caspase activity.

KEYWORDS Apoptosis; Gene therapy; Hypoxia/anoxia; Oxidative phosphorylation; Reperfusion


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