Harold D Schultz

University of Nebraska Medical Center, Cellular & Integrative Physiology

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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; et al. (Profiled Authors: Tatiana K Bronich; Lie Gao; Harold D Schultz; Matthew C Zimmerman; Irving H Zucker)

Biomaterials 2010;31(19):5218-5226.

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. © 2010 Elsevier Ltd.

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