Eicosanoid Signaling and Vascular Dysfunction: Methylmercury-Induced Phospholipase D Activation in Vascular Endothelial Cells

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 activatio...

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Bibliographic Details
Published in:	Cell biochemistry and biophysics Vol. 67; no. 2; pp. 317 - 329
Main Authors:	Sherwani, Shariq I., Pabon, Sheila, Patel, Rishi B., Sayyid, Muzzammil M., Hagele, Thomas, Kotha, Sainath R., Magalang, Ulysses J., Maddipati, Krishna R., Parinandi, Narasimham L.
Format:	Journal Article
Language:	English
Published:	Boston Springer US 01-11-2013 Springer Nature B.V
Subjects:	Animals Biocatalysis Biochemistry Biological and Medical Physics Biomedical and Life Sciences Biophysics Biotechnology Blood Vessels - drug effects Blood Vessels - pathology Blood Vessels - physiopathology Cardiovascular diseases Cattle Cell Biology Cytotoxicity Dose-Response Relationship, Drug Eicosanoids - biosynthesis Eicosanoids - metabolism Endothelial Cells - cytology Endothelial Cells - drug effects Endothelial Cells - metabolism Endothelial Cells - secretion Enzyme Activation - drug effects Enzyme Inhibitors - pharmacology L-Lactate Dehydrogenase - secretion Life Sciences Lipoxygenase - metabolism Mercury Methylmercury Methylmercury Compounds - pharmacology Original Paper Oxidative stress Pharmacology/Toxicology Phospholipase D - metabolism Phospholipases A2 - metabolism Phosphorylation - drug effects Prostaglandin-Endoperoxide Synthases - metabolism Pulmonary Artery - cytology Serine - metabolism Signal Transduction - drug effects Time Factors Upstream Vascular endothelial cells Cyclooxygenase Eicosanoid signaling PLD Lipoxygenase Phospholipase A Phospholipase D
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Summary:	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 [ 3 H]arachidonic acid, AA) and PLD (formation of [ 32 P]phosphatidylbutanol) in BPAECs in dose- (0–10 μM) and time-dependent (0–60 min) fashion. The cPLA 2 -specific inhibitor, arachidonyl trifluoromethyl ketone (AACOCF 3 ), significantly attenuated the MeHg-induced [ 3 H]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.
ISSN:	1085-9195 1559-0283
DOI:	10.1007/s12013-011-9304-3