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International Journal of Toxicology
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Articles

Calcium and Calmodulin Regulate Mercury-induced Phospholipase D Activation in Vascular Endothelial Cells

Alon Peltz
Shariq I. Sherwani
Sainath R. Kotha
Jessica N. Mazerik
Elizabeth S. O’Connor Butler
M. Lakshmi Kuppusamy
Thomas Hagele
Ulysses J. Magalang
Periannan Kuppusamy
Clay B. Marsh
Narasimham L. Parinandi

From the Lipid Signaling and Lipidomics Laboratory, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, Ohio, 43210, USA.

Correspondence: Please address correspondence to Narasimham L. Parinandi, PhD, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, 473 W. 12th Ave, Columbus, OH 43210; e-mail:narasimham.parinandi{at}osumc.edu.

Earlier, we reported that mercury, the environmental risk factor for cardiovascular diseases, activates vascular endothelial cell (EC) phospholipase D (PLD). Here, we report the novel and significant finding that calcium and calmodulin regulated mercury-induced PLD activation in bovine pulmonary artery ECs (BPAECs). Mercury (mercury chloride, 25 µM; thimerosal, 25 µM; methylmercury, 10 µM) significantly activated PLD in BPAECs. Calcium chelating agents and calcium depletion of the medium completely attenuated the mercury-induced PLD activation in ECs. Calmodulin inhibitors significantly attenuated mercury-induced PLD activation in BPAECs. Despite the absence of L-type calcium channels in ECs, nifedipine, nimodipine, and diltiazem significantly attenuated mercury-induced PLD activation and cytotoxicity in BPAECs. This study demonstrated the importance of calcium and calmodulin in the regulation of mercury-induced PLD activation and the protective action of L-type calcium channel blockers against mercury cytotoxicity in vascular ECs, suggesting mechanisms of mercury vasculotoxicity and mercury-induced cardiovascular diseases.

Key Words: calcium • calmodulin • L-type calcium channel blockers • lipid signaling • mercury • phospholipase D • phosphatidic acid • vascular endothelial cells

International Journal of Toxicology, Vol. 28, No. 3, 190-206 (2009)
DOI: 10.1177/1091581809338077
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