title: Rat H9c2 cardiac myocytes are sensitive to arsenite due to a modest activation of transcription factor Nrf2.
abstract: The mechanism underlying the hepatotoxicity induced by arsenic exposure is well investigated. However, little is known about the detailed mechanisms of arsenic-induced cardiotoxicity or cardiac factors involved in high sensitivity to arsenicals in spite of the fact that arsenic trioxide, which is used to treat acute promyelocytic leukemia, causes cardiotoxicity. Here, we show that rat H9c2(2-1) cardiac myocytes exhibit high sensitivity to inorganic arsenite (As(III)) as compared with rat-derived four cell lines (liver epithelial TRL1215 cells, kidney epithelial NRK-52E cells, PC12 phechromocytoma cells and C6 glioma cells). Furthermore, we found a lower steady-state level of glutathione and glutamyl-cysteine ligase (GCL) in H9c2(2-1) cells compared with TRL1215 cells, resulting in an increase in arsenic accumulation. In addition, we detected that the up-regulation of GCL and multi-drug resistance-associated protein (MRP) caused by As(III) was extremely low in H9c2(2-1) cells compared with TRL1215 cells. It is known that Nrf2, which regulates GCL and MRP expression, plays an important role in the protection of cells from arsenicals. We investigated the participation of Nrf2 in the difference of sensitivity to arsenicals between H9c2(2-1) and TRL1215 cells and found that Nrf2 was clearly activated by As(III) exposure in TRL1215 cells but only poorly activated in H9c2(2-1) cells. Considering these results together, we propose that modest activation of Nrf2 during exposure to As(III) in H9c2(2-1) cardiac myocytes leads to reduced ability to metabolize and excrete arsenic.
authors.affiliation: Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan.
authors.forename: Daigo
authors.initials: D
authors.lastname: Sumi
authors.forename: Takahiko
authors.initials: T
authors.lastname: Sasaki
authors.forename: Hideki
authors.initials: H
authors.lastname: Miyataka
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Himeno
mesh_terms: D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D002460:Cell Line; D002478:Cells, Cultured; D004785:Environmental Pollutants / Q000633:toxicity; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D051381:Rats; D017670:Sodium Compounds / Q000633:toxicity*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018053:Arsenites; D004785:Environmental Pollutants; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D051267:NF-E2-Related Factor 2; D017670:Sodium Compounds; C017947:sodium arsenite