title: Over-expressed copper/zinc superoxide dismutase localizes to mitochondria in neurons inhibiting the angiotensin II-mediated increase in mitochondrial superoxide.
abstract: Angiotensin II (AngII) is the main effector peptide of the renin-angiotensin system (RAS), and contributes to the pathogenesis of cardiovascular disease by exerting its effects on an array of different cell types, including central neurons. AngII intra-neuronal signaling is mediated, at least in part, by reactive oxygen species, particularly superoxide (O2 (•-)). Recently, it has been discovered that mitochondria are a major subcellular source of AngII-induced O2 (•-). We have previously reported that over-expression of manganese superoxide dismutase (MnSOD), a mitochondrial matrix-localized O2 (•-) scavenging enzyme, inhibits AngII intra-neuronal signaling. Interestingly, over-expression of copper/zinc superoxide dismutase (CuZnSOD), which is believed to be primarily localized to the cytoplasm, similarly inhibits AngII intra-neuronal signaling and provides protection against AngII-mediated neurogenic hypertension. Herein, we tested the hypothesis that CuZnSOD over-expression in central neurons localizes to mitochondria and inhibits AngII intra-neuronal signaling by scavenging mitochondrial O2 (•-). Using a neuronal cell culture model (CATH.a neurons), we demonstrate that both endogenous and adenovirus-mediated over-expressed CuZnSOD (AdCuZnSOD) are present in mitochondria. Furthermore, we show that over-expression of CuZnSOD attenuates the AngII-mediated increase in mitochondrial O2 (•-) levels and the AngII-induced inhibition of neuronal potassium current. Taken together, these data clearly show that over-expressed CuZnSOD in neurons localizes in mitochondria, scavenges AngII-induced mitochondrial O2 (•-), and inhibits AngII intra-neuronal signaling.
authors.affiliation: Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Shumin
authors.initials: S
authors.lastname: Li
authors.affiliation: Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Case
authors.affiliation: Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Rui-Fang
authors.initials: RF
authors.lastname: Yang
authors.affiliation: Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA ; Redox Biology Center, University of Nebraska - Lincoln, Lincoln, NE, USA.
authors.forename: Harold D
authors.initials: HD
authors.lastname: Schultz
authors.affiliation: Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA ; Redox Biology Center, University of Nebraska - Lincoln, Lincoln, NE, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Zimmerman
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D005822:Genetic Vectors / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*
chemical_list: D013481:Superoxides; D000804:Angiotensin II; D013482:Superoxide Dismutase
keywords: AT1R, angiotensin type 1 receptor; AngII, angiotensin II; Angiotensin II; CuZnSOD; CuZnSOD, copper/zinc superoxide dismutase; Ikv, neuronal potassium current; MIMS, mitochondrial inter-membrane space; Mitochondria; MnSOD, manganese superoxide dismutase; NOX, NADPH oxidase; Neurons; Potassium current; RAS, renin–angiotensin system; ROS, reactive oxygen species; Superoxide