title: Augmentation of poly(ADP-ribose) polymerase-dependent neuronal cell death by acidosis.
abstract: Tissue acidosis is a key component of cerebral ischemic injury, but its influence on cell death signaling pathways is not well defined. One such pathway is parthanatos, in which oxidative damage to DNA results in activation of poly(ADP-ribose) polymerase and generation of poly(ADP-ribose) polymers that trigger release of mitochondrial apoptosis-inducing factor. In primary neuronal cultures, we first investigated whether acidosis per sé is capable of augmenting parthanatos signaling initiated pharmacologically with the DNA alkylating agent, N-methyl- N'-nitro- N-nitrosoguanidine. Exposure of neurons to medium at pH 6.2 for 4 h after N-methyl- N'-nitro- N-nitrosoguanidine washout increased intracellular calcium and augmented the N-methyl- N'-nitro- N-nitrosoguanidine-evoked increase in poly(ADP-ribose) polymers, nuclear apoptosis-inducing factor , and cell death. The augmented nuclear apoptosis-inducing factor and cell death were blocked by the acid-sensitive ion channel-1a inhibitor, psalmotoxin. In vivo, acute hyperglycemia during transient focal cerebral ischemia augmented tissue acidosis, poly(ADP-ribose) polymers formation, and nuclear apoptosis-inducing factor , which was attenuated by a poly(ADP-ribose) polymerase inhibitor. Infarct volume from hyperglycemic ischemia was decreased in poly(ADP-ribose) polymerase 1-null mice. Collectively, these results demonstrate that acidosis can directly amplify neuronal parthanatos in the absence of ischemia through acid-sensitive ion channel-1a . The results further support parthanatos as one of the mechanisms by which ischemia-associated tissue acidosis augments cell death.
authors.affiliation: 1 Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 1 Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.affiliation: 1 Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Herman
authors.initials: H
authors.lastname: Kwansa
authors.affiliation: 1 Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, MD, USA.|2 Division of Metabolism and Functionality Research, Korea Food Research Institute, Sungham City, Republic of Korea.
authors.forename: Yun Tai
authors.initials: YT
authors.lastname: Kim
authors.affiliation: 1 Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Liye
authors.initials: L
authors.lastname: Yi
authors.affiliation: 1 Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Gina
authors.initials: G
authors.lastname: Hong
authors.affiliation: 3 Neuroregeneration and Stem Cell Programs, The Institute of Cell Engineering, The Johns Hopkins University, Baltimore, MD, USA.|4 Department of Neurology, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Shaida A
authors.initials: SA
authors.lastname: Andrabi
authors.affiliation: 4 Department of Neurology, The Johns Hopkins University, Baltimore, MD, USA.|5 Department of Neuroscience, The Johns Hopkins University, Baltimore, MD, USA.|6 Department of Physiology, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
authors.affiliation: 3 Neuroregeneration and Stem Cell Programs, The Institute of Cell Engineering, The Johns Hopkins University, Baltimore, MD, USA.|4 Department of Neurology, The Johns Hopkins University, Baltimore, MD, USA.|5 Department of Neuroscience, The Johns Hopkins University, Baltimore, MD, USA.|7 Department of Pharmacology and Molecular Sciences, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
authors.affiliation: 1 Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Koehler
authors.affiliation: 1 Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Zeng-Jin
authors.initials: ZJ
authors.lastname: Yang
mesh_terms: D000138:Acidosis / Q000201:enzymology / Q000473:pathology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004249:DNA Damage; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D061251:Primary Cell Culture
chemical_list: D051017:Apoptosis Regulatory Proteins; D008769:Methylnitronitrosoguanidine; D011065:Poly(ADP-ribose) Polymerases; D002118:Calcium
keywords: Brain ischemia; cell culture; cell death mechanisms; hyperglycemia; stroke