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Phospholipase A₂ Activation Regulates Cytotoxicity of Methylmercury in Vascular Endothelial Cells

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, USA

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

Mercury has been identified as a risk factor for cardiovascular disease among humans. Through diet, mainly fish consumption, humans are exposed to methylmercury, the biomethylated organic form of environmental mercury. As the endothelium is an important player in homeostasis of the cardiovascular system, here, the authors tested their hypothesis that methylmercury activates the lipid signaling enzyme phospholipase A₂ (PLA₂) in vascular endothelial cells (ECs), causing upstream regulation of cytotoxicity. To test this hypothesis, the authors used bovine pulmonary artery ECs (BPAECs) cultured in monolayers, following labeling of their membrane phospholipids with [³H]arachidonic acid (AA). The cells were exposed to methylmercury chloride (MMC) and then the release of free AA (index of PLA₂ activity) and lactate dehydrogenase (LDH; index of cytotoxicity) were determined by liquid scintillation counting and spectrophotometry, respectively. MMC significantly activated PLA₂ in a dose-dependent (5 to 15 µM) and time-dependent (0 to 60 min) fashion. Sulfhydryl (thiolprotective) agents, calcium chelators, antioxidants, and PLA₂-specific inhibitors attenuated the MMC-induced PLA₂ activation, suggesting the role of thiols, reactive oxygen species (ROS), and calcium in the activation of PLA₂ in BPAECs. MMC also induced the loss of thiols and increase of lipid peroxidation in BPAECs. MMC induced cytotoxicity in BPAECs as observed by the altered cell morphology and LDH leak, which was significantly attenuated by PLA₂ inhibitors. This study established that PLA₂ activation through thiols, calcium, and oxidative stress was associated with the cytotoxicity of MMC in BPAECs, drawing attention to the involvement of PLA₂ signaling in the methylmercury-induced vascular endothelial dysfunctions.

Key Words: Arachidonic Acid • Environmental Cardiovascular Risk • Lipid Signaling • Methylmercury • Phospholipase A₂ • Vascular Endothelial Cell

International Journal of Toxicology, Vol. 26, No. 6, 553-569 (2007)
DOI: 10.1080/10915810701707759


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