title: The attenuation of central angiotensin II-dependent pressor response and intra-neuronal signaling by intracarotid injection of nanoformulated copper/zinc superoxide dismutase.
abstract: Adenoviral-mediated overexpression of the intracellular superoxide (O(2)(*-)) scavenging enzyme copper/zinc superoxide dismutase (CuZnSOD) in the brain attenuates central angiotensin II (AngII)-induced cardiovascular responses. However, the therapeutic potential for adenoviral vectors is weakened by toxicity and the inability of adenoviral vectors to target the brain following peripheral administration. Therefore, we developed a non-viral delivery system in which CuZnSOD protein is electrostatically bound to a synthetic poly(ethyleneimine)-poly(ethyleneglycol) (PEI-PEG) polymer to form a polyion complex (CuZnSOD nanozyme). We hypothesized that PEI-PEG polymer increases transport of functional CuZnSOD to neurons, which inhibits AngII intra-neuronal signaling. The AngII-induced increase in O(2)(*-), as measured by dihydroethidium fluorescence and electron paramagnetic resonance spectroscopy, was significantly inhibited in CuZnSOD nanozyme-treated neurons compared to free CuZnSOD- and non-treated neurons. CuZnSOD nanozyme also attenuated the AngII-induced inhibition of K(+) current in neurons. Intracarotid injection of CuZnSOD nanozyme into rabbits significantly inhibited the pressor response of intracerebroventricular-delivered AngII; however, intracarotid injection of free CuZnSOD or PEI-PEG polymer alone failed to inhibit this response. Importantly, neither the PEI-PEG polymer alone nor the CuZnSOD nanozyme induced neuronal toxicity. These findings indicate that CuZnSOD nanozyme inhibits AngII intra-neuronal signaling in vitro and in vivo.
authors.affiliation: Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA.
authors.forename: Erin G
authors.initials: EG
authors.lastname: Rosenbaugh
authors.forename: James W
authors.initials: JW
authors.lastname: Roat
authors.forename: Lie
authors.initials: L
authors.lastname: Gao
authors.forename: Rui-Fang
authors.initials: RF
authors.lastname: Yang
authors.forename: Devika S
authors.initials: DS
authors.lastname: Manickam
authors.forename: Jing-Xiang
authors.initials: JX
authors.lastname: Yin
authors.forename: Harold D
authors.initials: HD
authors.lastname: Schultz
authors.forename: Tatiana K
authors.initials: TK
authors.lastname: Bronich
authors.forename: Elena V
authors.initials: EV
authors.lastname: Batrakova
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Kabanov
authors.forename: Irving H
authors.initials: IH
authors.lastname: Zucker
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Zimmerman
mesh_terms: D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000818:Animals; D002344:Carotid Body / Q000187:drug effects*; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011817:Rabbits; D013482:Superoxide Dismutase / Q000008:administration & dosage* / Q000737:chemistry*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D004337:Drug Carriers; D000804:Angiotensin II; D013482:Superoxide Dismutase