title: Involvement of Bid and caspase-2 in endoplasmic reticulum stress- and oxidative stress-induced retinal ganglion cell death.
abstract: Endoplasmic reticulum (ER) stress and oxidative stress are involved in many diseases, including retinal disorders, causing toxicity in various tissues and cells; however, intracellular signaling of ER stress and cross-talk between ER stress and oxidative stress are unknown in retinal ganglion cells (RGC), whose degeneration is associated with glaucoma. The aim of the study was to clarify the mechanisms of ER stress- and oxidative stress-induced RGC death, using cultured retinal ganglion cells (RGC-5) in vitro and N-methyl-D-aspartate (NMDA)- or ER stress-induced retinal damage in mice in vivo. We focused on both BH3-interacting domain death agonist (Bid) and caspase-2, which work as apoptosis promotion factors. In an in vitro study, both Bid and caspase-2 inhibitors protected against RGC-5 death from ER stress or oxidative stress. A caspase-2 inhibitor did not inhibit Bid cleavage, although a Bid inhibitor reduced the increase of caspase-2 activity in ER stress-induced RGC-5 death. A Bid inhibitor also reduced the increase of caspase-2 activity in oxidative stress-induced RGC-5 death. Moreover, both Bid and caspase-2 inhibitors reduced the increase of caspase-3 activity. In an in vivo study, a Bid inhibitor inhibited NMDA- or ER stress-induced retinal damage. These findings indicate that a common mechanism through Bid and caspase-2 exists in both ER stress- and oxidative stress-induced RGC death and that they are activated in the order of Bid, caspase-2, and caspase-3.
authors.affiliation: Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Rumi
authors.initials: R
authors.lastname: Uchibayashi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsuruma
authors.forename: Yuta
authors.initials: Y
authors.lastname: Inokuchi
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Shimazawa
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
mesh_terms: D000818:Animals; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D053143:Caspase 2 / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism*
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D016202:N-Methylaspartate; D053143:Caspase 2