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International Journal of Toxicology
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Article

Mercury Activates Vascular Endothelial Cell Phospholipase D through Thiols and Oxidative Stress

Thomas J. Hagele
Jessica N. Mazerik
Anita Gregory
Bruce Kaufman
Ulysses Magalang
M. Lakshmi Kuppusamy
Clay B. Marsh
Periannan Kuppusamy
Narasimham L. Parinandi

Lipidomics and Lipid Signaling Laboratory, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, Ohio, United States

Correspondence: Address correspondence to Narasimham L. Parinandi, PhD, Room 611-A, Division of Pulmonary, Critical Care, and Sleep Medicine, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, 473 W. 12th Avenue, Columbus, OH 43210, USA. E-mail:narasimham.parinandi{at}osumc.edu

Currently, mercury has been identified as a risk factor of cardiovascular diseases among humans. Here, the authors tested the hypothesis that mercury modulates the activity of the endothelial lipid signaling enzyme, phospholipase D (PLD), which is an important player in the endothelial cell (EC) barrier functions. Monolayers of bovine pulmonary artery ECs (BPAECs) in culture, following labeling of membrane phospholipids with [32P]orthophosphate, were exposed to mercuric chloride (inorganic form), methylmercury chloride (environmental form), and thimerosal (pharmaceutical form), and the formation of phosphatidylbutanol as an index of PLD activity was determined by thin-layer chromatography and liquid scintillation counting. All three forms of mercury significantly activated PLD in BPAECs in a dose-dependent (0 to 50 µM) and time-dependent (0 to 60 min) fashion. Metal chelators significantly attenuated mercury-induced PLD activation, suggesting that cellular mercury-ligand interaction(s) is required for the enzyme activation and that chelators are suitable blockers for mercury-induced PLD activation. Sulfhydryl (thiol-protective) agents and antioxidants also significantly attenuated the mercury-induced PLD activation in BPAECs. Enhanced reactive oxygen species generation, as an index of oxidative stress, was observed in BPAECs treated with methylmercury that was attenuated by antioxidants. All the three different forms of mercury significantly induced the decrease of levels of total cellular thiols. For the first time, this study revealed that mercury induced the activation of PLD in the vascular ECs wherein cellular thiols and oxidative stress acted as signal mediators for the enzyme activation. The results underscore the importance of PLD signaling in mercury-induced endothelial dysfunctions ultimately leading to cardiovascular diseases.

Key Words: Lipid Signaling • Mercury • Oxidative Stress • Phospholipase D • Reactive Oxygen Species • Vascular Endothelial Cells

International Journal of Toxicology, Vol. 26, No. 1, 57-69 (2007)
DOI: 10.1080/10915810601120509
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