Carbon monoxide-releasing molecule CORM-3 suppresses vascular endothelial cell SOD-1/SOD-2 activity while up-regulating the cell surface levels of SOD-3 in a heparin-dependent manner

The role of CO in the modulation of antioxidant enzyme function has not been investigated, yet. In this study we assessed the effects and potential mechanisms of the ruthenium-based water-soluble CO-releasing molecule CORM-3 in the modulation of superoxide dismutase (SOD) activity/binding in vascula...

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Published in:	Free radical biology & medicine 2010-11, Vol.49 (10), p.1534-1541
Main Authors:	Mizuguchi, Shinjiro, Capretta, Alfredo, Suehiro, Shigefumi, Nishiyama, Noritoshi, Luke, Patrick, Potter, Richard F., Fraser, Douglas D., Cepinskas, Gediminas
Format:	Article
Language:	eng
Subjects:	Antioxidant enzymes Carbon Monoxide - pharmacology Cell culture Cell-Free System - metabolism Cells, Cultured Endothelial Cells - drug effects Endothelial Cells - enzymology Free radicals Heparin Heparin - pharmacology Humans Inflammation Organometallic Compounds - pharmacology Oxidative stress Superoxide Dismutase - antagonists & inhibitors Superoxide Dismutase - metabolism Superoxide Dismutase-1 Up-Regulation Vascular endothelium
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Summary:	The role of CO in the modulation of antioxidant enzyme function has not been investigated, yet. In this study we assessed the effects and potential mechanisms of the ruthenium-based water-soluble CO-releasing molecule CORM-3 in the modulation of superoxide dismutase (SOD) activity/binding in vascular endothelial cells (HUVECs). To this end, HUVECs were treated with CORM-3 (100 μM) and assessed for total SOD activity in cell lysates (cell-associated SOD activity) and cell culture supernatants (soluble SOD). In parallel, release/binding of extracellular SOD (SOD-3) in the absence or presence of heparin (1–10 IU/ml), a key factor regulating SOD-3 cell-surface binding, was investigated. In addition, the effects of CORM-3 on the modulation of purified SOD-1 and SOD-2 activity in a cell-free system were also assessed. The results obtained indicate that CORM-3 effectively suppresses the activity of both purified SOD-1 and SOD-2. These findings were accompanied by CORM-3-dependent attenuation of total cell-associated SOD activity (without affecting SOD-1/SOD-2 protein expression) and a subsequent increase in ROS production (DHR123 oxidation) in HUVECs. In parallel, a concomitant increase in soluble-SOD activity (due to increased SOD-3 release from the cell surface) was observed in the cell culture supernatants. However, in the presence of heparin, total cell-associated SOD activity was significantly increased by CORM-3, because of increased binding of SOD-3 to HUVECs. Taken together these findings indicate for the first time that CORM-3 modulates both the activity of intracellular SOD (i.e., SOD-1 and SOD-2) and the binding of extracellular SOD (SOD-3) to the cell surface.
ISSN:	0891-5849 1873-4596