The attenuation of central angiotensin II-dependent pressor response and intra-neuronal signaling by intracarotid injection of nanoformulated copper/zinc superoxide dismutase

Erin G. Rosenbaugh, James W. Roat, Lie Gao, Rui Fang Yang, Devika S. Manickam, Jing Xiang Yin, Harold D Schultz, Tatiana K Bronich, Elena V. Batrakova, Alexander V. Kabanov, Irving H Zucker, Matthew C Zimmerman

Research output: Contribution to journalArticle

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Abstract

Adenoviral-mediated overexpression of the intracellular superoxide (O2·-) 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 O2·-, 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.

Original languageEnglish (US)
Pages (from-to)5218-5226
Number of pages9
JournalBiomaterials
Volume31
Issue number19
DOIs
StatePublished - Jul 1 2010

Fingerprint

Angiotensin II
Neurons
Superoxide Dismutase
Zinc
Copper
Injections
Polymers
Toxicity
Brain
Scavenging
Paramagnetic resonance
Enzymes
Fluorescence
Electron Spin Resonance Spectroscopy
Spectroscopy
Proteins
Superoxides
Spectrum Analysis
Rabbits
aziridine

Keywords

  • Brain
  • Copolymer
  • Drug delivery
  • Nanotechnology
  • Potassium current
  • Superoxide dismutase

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

Cite this

The attenuation of central angiotensin II-dependent pressor response and intra-neuronal signaling by intracarotid injection of nanoformulated copper/zinc superoxide dismutase. / Rosenbaugh, Erin G.; Roat, James W.; Gao, Lie; Yang, Rui Fang; Manickam, Devika S.; Yin, Jing Xiang; Schultz, Harold D; Bronich, Tatiana K; Batrakova, Elena V.; Kabanov, Alexander V.; Zucker, Irving H; Zimmerman, Matthew C.

In: Biomaterials, Vol. 31, No. 19, 01.07.2010, p. 5218-5226.

Research output: Contribution to journalArticle

Rosenbaugh, Erin G. ; Roat, James W. ; Gao, Lie ; Yang, Rui Fang ; Manickam, Devika S. ; Yin, Jing Xiang ; Schultz, Harold D ; Bronich, Tatiana K ; Batrakova, Elena V. ; Kabanov, Alexander V. ; Zucker, Irving H ; Zimmerman, Matthew C. / The attenuation of central angiotensin II-dependent pressor response and intra-neuronal signaling by intracarotid injection of nanoformulated copper/zinc superoxide dismutase. In: Biomaterials. 2010 ; Vol. 31, No. 19. pp. 5218-5226.
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AU - Yang, Rui Fang

AU - Manickam, Devika S.

AU - Yin, Jing Xiang

AU - Schultz, Harold D

AU - Bronich, Tatiana K

AU - Batrakova, Elena V.

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AU - Zucker, Irving H

AU - Zimmerman, Matthew C

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