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 activation through the upstream regulation by phospholipase A2 (PLA2) 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 PLA2 (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 cPLA2-specific inhibitor, arachidonyl trifluoromethyl ketone (AACOCF3), significantly attenuated the MeHg-induced [(3)H]AA release in ECs. MeHg-induced PLD activation was also inhibited by AACOCF3 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 PLA2-, 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 cPLA2 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.
Lipidomics, Lipid Signaling, and Vasculotoxicity Laboratory, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, 473 W. 12th Avenue, Columbus, OH, 43210, USA.
Shariq I
SI
Sherwani
Sheila
S
Pabon
Rishi B
RB
Patel
Muzzammil M
MM
Sayyid
Thomas
T
Hagele
Sainath R
SR
Kotha
Ulysses J
UJ
Magalang
Krishna R
KR
Maddipati
Narasimham L
NL
Parinandi
D000818:Animals; D055162:Biocatalysis; D001808:Blood Vessels / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D015777:Eicosanoids / Q000096:biosynthesis / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008084:Lipoxygenase / Q000378:metabolism; D008767:Methylmercury Compounds / Q000494:pharmacology*; D010739:Phospholipase D / Q000378:metabolism*; D054467:Phospholipases A2 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
D015777:Eicosanoids; D004791:Enzyme Inhibitors; D008767:Methylmercury Compounds; D012694:Serine; D007770:L-Lactate Dehydrogenase; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D054467:Phospholipases A2; D010739:Phospholipase D