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1 Vascular Biology Center, Medical College of Georgia, Augusta, Georgia, United States
2 Biomedical and Pharmaceutical Sciences, THe University of Montana, Missoula, Montana, United States
* To whom correspondence should be addressed. E-mail: Sblack{at}mail.mcg.edu.
Oxidative stress is associated with multiple pathologies including those involving the cardiovascular system. Previously, we have shown that pulmonary artery endothelial cells (PAECs) undergo apoptosis following acute exposure to hydrogen peroxide (H2O2). However, the underlying mechanisms regulating this remain unclear. Given the prevalence of H2O2 in normal physiological processes and apparent loss of regulation in disease states, the purpose of this study was to develop a more complete understanding of H2O2-mediated adverse effects on endothelial cell survival. Our data indicate that PAECs acutely exposed to H2O2 exhibit a dose-dependent increase in release of lactate dehydrogenase and increased production of superoxide ions (O2.) generated within the mitochondria. In addition, PAECs exhibited significant loss of mitochondrial membrane potential (m
) and activity. Subsequent to the loss of m, PAECs exhibited significant caspase activation and apoptotic nuclei. We also observed a significant increase in intracellular free zinc (Zn2+) following exposure to H2O2. We next determined if this increase in Zn2+ was involved in the apoptotic pathway induced by H2O2 exposure. Our data indicate that chelating Zn2+ ions, either pharmacologically with N,N,N',N-tetrakis[2-pyridylmethyl] ethylenediamine (TPEN) or by overexpression of the Zn2+-binding protein metallothionein-1 (MT-1) in PAECs conferred protection from induction of apoptosis and cell death associated with the effects of H2O2 exposure. In conclusion, our results show that the acute toxicity profile of H2O2 can be attributed, at least in part, to liberation of Zn2+. We speculate that regulation of Zn2+ levels may represent a potential therapeutic target for cardiovascular disease associated with acute oxidative stress.
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