title: Calcium-dependent nitric oxide production is involved in the cytoprotective properties of n-acetylcysteine in glycochenodeoxycholic acid-induced cell death in hepatocytes.
abstract: The intracellular oxidative stress has been involved in bile acid-induced cell death in hepatocytes. Nitric oxide (NO) exerts cytoprotective properties in glycochenodeoxycholic acid (GCDCA)-treated hepatocytes. The study evaluated the involvement of Ca2+ on the regulation of NO synthase (NOS)-3 expression during N-acetylcysteine (NAC) cytoprotection against GCDCA-induced cell death in hepatocytes. The regulation of Ca2+ pools (EGTA or BAPTA-AM) and NO (L-NAME or NO donor) production was assessed during NAC cytoprotection in GCDCA-treated HepG2 cells. The stimulation of Ca2+ entrance was induced by A23187 in HepG2. Cell death, Ca2+ mobilization, NOS-1, -2 and -3 expression, AP-1 activation, and NO production were evaluated. GCDCA reduced intracellular Ca2+ concentration and NOS-3 expression, and enhanced cell death in HepG2. NO donor prevented, and l-NAME enhanced, GCDCA-induced cell death. The reduction of Ca2+ entry by EGTA, but not its release from intracellular stores by BAPTA-AM, enhanced cell death in GCDCA-treated cells. The stimulation of Ca2+ entrance by A23187 reduced cell death and enhanced NOS-3 expression in GCDCA-treated HepG2 cells. The cytoprotective properties of NAC were related to the recovery of intracellular Ca2+ concentration, NOS-3 expression and NO production induced by GCDCA-treated HepG2 cells. The increase of NO production by Ca2+-dependent NOS-3 expression during NAC administration reduces cell death in GCDCA-treated hepatocytes.
authors.affiliation: Liver Research Unit, Reina Sofía University Hospital, Córdoba, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: González-Rubio
authors.forename: Clara I
authors.initials: CI
authors.lastname: Linares
authors.forename: Rosario I
authors.initials: RI
authors.lastname: Bello
authors.forename: Raul
authors.initials: R
authors.lastname: González
authors.forename: Gustavo
authors.initials: G
authors.lastname: Ferrín
authors.forename: Ana B
authors.initials: AB
authors.lastname: Hidalgo
authors.forename: Elisa
authors.initials: E
authors.lastname: Muñoz-Gomariz
authors.forename: Blanca A
authors.initials: BA
authors.lastname: Rodríguez
authors.forename: Pilar
authors.initials: P
authors.lastname: Barrera
authors.forename: Isidora
authors.initials: I
authors.lastname: Ranchal
authors.forename: Mario
authors.initials: M
authors.lastname: Durán-Prado
authors.forename: Patricia
authors.initials: P
authors.lastname: Aguilar-Melero
authors.forename: Manuel
authors.initials: M
authors.lastname: De la Mata
authors.forename: Jordi
authors.initials: J
authors.lastname: Muntané
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D005999:Glycochenodeoxycholic Acid / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D009569:Nitric Oxide / Q000096:biosynthesis*; D009838:Oligodeoxyribonucleotides
chemical_list: D009838:Oligodeoxyribonucleotides; D009569:Nitric Oxide; D005999:Glycochenodeoxycholic Acid; D002118:Calcium; D000111:Acetylcysteine