Journal
CELL BIOCHEMISTRY AND BIOPHYSICS
Volume 67, Issue 2, Pages 317-329Publisher
HUMANA PRESS INC
DOI: 10.1007/s12013-011-9304-3
Keywords
Cyclooxygenase; Lipoxygenase; Phospholipase D; Eicosanoid signaling; Phospholipase A(2); Vascular endothelial cells; PLD
Funding
- International Academy of Oral Medicine and Toxicology (IA-OMT)
- Davis Heart and Lung Research Institute
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine
- National Institutes of Health [HL 093463]
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Mercury, especially methylmercury (MeHg), is implicated in the etiology of cardiovascular diseases. Earlier, we have reported that MeHg induces phospholipase D (PLD) activation through oxidative stress and thiol-redox alteration. Hence, we investigated the mechanism of the MeHg-induced PLD activation through the upstream regulation by phospholipase A(2) (PLA(2)) and lipid oxygenases such as cyclooxygenase (COX) and lipoxygenase (LOX) in the bovine pulmonary artery endothelial cells (BPAECs). Our results showed that MeHg significantly activated both PLA(2) (release of [H-3]arachidonic acid, AA) and PLD (formation of [P-32]phosphatidylbutanol) in BPAECs in dose- (0-10 mu M) and time-dependent (0-60 min) fashion. The cPLA(2)-specific inhibitor, arachidonyl trifluoromethyl ketone (AACOCF(3)), significantly attenuated the MeHg-induced [H-3]AA release in ECs. MeHg-induced PLD activation was also inhibited by AACOCF(3) and the COX- and LOX-specific inhibitors. MeHg also induced the formation of COX- and LOX-catalyzed eicosanoids in ECs. MeHg-induced cytotoxicity (based on lactate dehydrogenase release) was protected by PLA(2)-, COX-, and LOX-specific inhibitors and 1-butanol, the PLD-generated PA quencher. For the first time, our studies showed that MeHg activated PLD in vascular ECs through the upstream action of cPLA(2) and the COX- and LOX-generated eicosanoids. These results offered insights into the mechanism(s) of the MeHg-mediated vascular endothelial cell lipid signaling as an underlying cause of mercury-induced cardiovascular diseases.
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