title: Mitochondrial-driven ubiquinone enhances extracellular calcium-dependent nitric oxide production and reduces glycochenodeoxycholic acid-induced cell death in hepatocytes.
abstract: Ca(2+) mobilization, nitric oxide (NO), and oxidative stress have been involved in cell death induced by hydrophobic bile acid in hepatocytes. The aim of the study was the elucidation of the effect of the antioxidant mitochondrial-driven ubiquinone (Mito Q) on the intracellular Ca(2+) concentration, NO production, and cell death in glycochenodeoxycholic acid (GCDCA)-treated HepG2 cells. The role of the regulation of the intracellular Ca(2+) concentration by Ca(2+) chelators (EGTA or BAPTA-AM), agonist of Ca(2+) entrance (A23187) or NO (L-NAME or NO donor), was assessed during Mito Q cytoprotection in GCDCA-treated HepG2 cells. Cell death, NO synthase (NOS)-1, -2, and -3 expression, Ca(2+) mobilization, and NO production were evaluated. GCDCA reduced the intracellular Ca(2+) 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 Ca(2+) entry by EGTA, but not its release from intracellular stores by BAPTA-AM, reduced the expression of NOS-3 and enhanced cell death in control and GCDCA-treated cells. Mito Q prevented the reduction of intracellular Ca(2+) concentration, NOS-3 expression, NO production, and cell death in GCDCA-treated HepG2 cells. The conclusion is that the recovery of Ca(2+)-dependent NOS-3 expression by Mito Q may be considered an additional cytoprotective property of an antioxidant.
authors.affiliation: Liver Research Unit, Reina Sofia University Hospital, Cordoba, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: González-Rubio
authors.forename: Ana B
authors.initials: AB
authors.lastname: Hidalgo
authors.forename: Gustavo
authors.initials: G
authors.lastname: Ferrín
authors.forename: Rosario I
authors.initials: RI
authors.lastname: Bello
authors.forename: Raul
authors.initials: R
authors.lastname: González
authors.forename: Manuel D
authors.initials: MD
authors.lastname: Gahete
authors.forename: Isidora
authors.initials: I
authors.lastname: Ranchal
authors.forename: Blanca A
authors.initials: BA
authors.lastname: Rodríguez
authors.forename: Pilar
authors.initials: P
authors.lastname: Barrera
authors.forename: Patricia
authors.initials: P
authors.lastname: Aguilar-Melero
authors.forename: Clara I
authors.initials: CI
authors.lastname: Linares
authors.forename: Justo P
authors.initials: JP
authors.lastname: Castaño
authors.forename: Victor M
authors.initials: VM
authors.lastname: Victor
authors.forename: Manuel
authors.initials: M
authors.lastname: De la Mata
authors.forename: Jordi
authors.initials: J
authors.lastname: Muntané
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D005999:Glycochenodeoxycholic Acid / Q000737:chemistry* / Q000633:toxicity; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D014451:Ubiquinone / Q000378:metabolism*
chemical_list: D014451:Ubiquinone; D009569:Nitric Oxide; D000001:Calcimycin; D005999:Glycochenodeoxycholic Acid; D052250:Nitric Oxide Synthase Type III; D053148:Caspase 3; D002118:Calcium