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1 Biomedical & Pharmaceutical Sciences, The University of Montana, Missoula, Montana, United States; The International Heart Institute, The University of Montana, Missoula, Montana, United States
2 Biomedical & Pharmaceutical Sciences, The University of Montana, Missoula, Montana, United States
* To whom correspondence should be addressed. E-mail: Sblack{at}mail.mcg.edu.
While NO-mediated biological interactions have been intensively studied, the underlying mechanisms of nitrosative stress with resulting pathology remain unclear. Previous studies have demonstrated that NO increases free zinc ions (Zn2+) within cells. However, the effects on endothelial cell survival have not been adequately resolved. Thus, the purpose of this study was to investigate the role of altered zinc homeostasis on endothelial cell survival. We confirmed the previously observed increase in free Zn2+ and induction of apoptosis in pulmonary artery endothelial cells (PAECs) exposed to Spermine NONOate. NO has many effects upon cell function and we wanted to specifically evaluate the effects mediated by zinc. To accomplish this we utilized the addition of zinc chloride (ZnCl2) to PAEC. We observed that Zn2+-exposed PAECs exhibited a dose-dependent increase in superoxide (O2._) generation localized to the mitochondria. Furthermore, we found Zn2+ exposed PAECs exhibited a significant reduction in mitochondrial membrane potential (m
), loss of cardiolipin from the inner leaflet, caspase activation and increases in TUNEL-positive cells. Further, using an adenoviral construct for the over-expression of the Zn2+-binding protein, metallothionein-1 (MT-1), we found either MT-1 over-expression or coincubation with a Zn2+-selective chelator, TPEN, we found MT-1 over-expression in PAECs significantly protected the mitochondria from both NO and Zn2+-mediated disruption and induction of apoptosis and cell death. In summary, our results indicate that a loss of Zn2+ homeostasis produces mitochondrial dysfunction, increased oxidative stress, and apoptotic cell death. Regulation of Zn2+ levels may represent a therapeutic target for disease associated with both nitrosative and oxidative stress.
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