title: Novel lipid-soluble thiol-redox antioxidant and heavy metal chelator, N,N'-bis(2-mercaptoethyl)isophthalamide (NBMI) and phospholipase D-specific inhibitor, 5-fluoro-2-indolyl des-chlorohalopemide (FIPI) attenuate mercury-induced lipid signaling leading to protection against cytotoxicity in aortic endothelial cells.
abstract: Here, we investigated thiol-redox-mediated phospholipase D (PLD) signaling as a mechanism of mercury cytotoxicity in mouse aortic endothelial cell (MAEC) in vitro model utilizing the novel lipid-soluble thiol-redox antioxidant and heavy metal chelator, N,N'-bis(2-mercaptoethyl)isophthalamide (NBMI) and the novel PLD-specific inhibitor, 5-fluoro-2-indolyl des-chlorohalopemide (FIPI). Our results demonstrated (i) mercury in the form of mercury(II) chloride, methylmercury, and thimerosal induced PLD activation in a dose- and time-dependent manner; (ii) NBMI and FIPI completely attenuated mercury- and oxidant-induced PLD activation; (iii) mercury induced upstream phosphorylation of extracellular-regulated kinase 1/2 (ERK1/2) leading to downstream threonine phosphorylation of PLD(1) which was attenuated by NBMI; (iv) mercury caused loss of intracellular glutathione which was restored by NBMI; and (v) NBMI and FIPI attenuated mercury- and oxidant-induced cytotoxicity in MAECs. For the first time, this study demonstrated that redox-dependent and PLD-mediated bioactive lipid signaling was involved in mercury-induced vascular EC cytotoxicity which was protected by NBMI and FIPI.
authors: Lipid Signaling, Lipidomics, and Vasculotoxicity Laboratory, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Dorothy M. Davis Heartand Lung Research Institute and Division of Pharmacology, Colleges of Medicineand Pharmacy, The Ohio State University, Columbus, OH, USA.
authors: Jordan D
authors: JD
authors: Secor
authors: Sainath R
authors: SR
authors: Kotha
authors: Travis O
authors: TO
authors: Gurney
authors: Rishi B
authors: RB
authors: Patel
authors: Nicholas R
authors: NR
authors: Kefauver
authors: Niladri
authors: N
authors: Gupta
authors: Andrew J
authors: AJ
authors: Morris
authors: Boyd E
authors: BE
authors: Haley
authors: Narasimham L
authors: NL
authors: Parinandi
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000494:pharmacology*; D001011:Aorta / Q000166:cytology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002614:Chelating Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D004294:Domperidone / Q000031:analogs & derivatives / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D050356:Lipid Metabolism; D008628:Mercury / Q000633:toxicity*; D051379:Mice; D010084:Oxidation-Reduction; D010739:Phospholipase D / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010795:Phthalic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013438:Sulfhydryl Compounds / Q000378:metabolism
chemical_list: C546435:5-fluoro-2-indolyldeschlorohalopemide; D000975:Antioxidants; D002614:Chelating Agents; D004785:Environmental Pollutants; D004791:Enzyme Inhibitors; D007211:Indoles; D010795:Phthalic Acids; D013438:Sulfhydryl Compounds; D004294:Domperidone; D007770:L-Lactate Dehydrogenase; D010739:Phospholipase D; D008628:Mercury