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ABSTRACT
Currently, mercury has been identified as a risk factor in cardiovascular diseases among humans. Here, we tested our hypothesis that mercury modulates the activity of the vascular endothelial cell (EC) lipid signaling enzyme phospholipase A2 (PLA2), which is an important player in the EC barrier functions. Monolayers of bovine pulmonary artery ECs (BPAECs) in culture, following labeling of membrane phospholipids with [3H]arachidonic acid (AA), were exposed to the inorganic form of mercury, mercury chloride, and the release of free AA (index of PLA2 activity) and formation of AA metabolites were determined by liquid scintillation counting and enzyme immunoassay, respectively. Mercury chloride significantly activated PLA2 in BPAECs in a dose-dependent (0 to 50 μM) and time-dependent (0 to 120 min) fashion. Metal chelators significantly attenuated mercury-induced PLA2 activation, suggesting that cellular mercury–ligand interaction is required for the enzyme activation and that chelators are suitable blockers for mercury-induced PLA2 activation in ECs. Sulfhydryl (thiol-protective) agents, calcium chelating agents, and cPLA2-specific inhibitor also significantly attenuated the mercury-induced PLA2, suggesting the role of thiol and calcium in the activation of cPLA2 in BPAECs. Significant formation of AA metabolites, including the release of total prostaglandins, thromboxane B2, and 8-isoprostane, were observed in BPAECs following their exposure to mercury chloride. Mercury chloride induced cytotoxicity as observed by the altered cell morphology and enhanced trypan blue uptake, which was attenuated by the cPLA2 inhibitor AACOCF3. The results of this study revealed that inorganic mercury-induced PLA2 activation through the thiol and calcium signaling and the formation of bioactive AA metabolites further demonstrated the association of PLA2 with the cytotoxicity of mercury in ECs. Overall, the results of the current study underscore the importance of PLA2 signaling in mercury-induced endothelial dysfunctions.