The attenuation of central angiotensin II-dependent pressor response and intra-neuronal signaling by intracarotid injection of nanoformulated copper/zinc superoxide dismutase.
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.
Rosenbaugh
Erin G
EG
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA.
Roat
James W
JW
Gao
Lie
L
Yang
Rui-Fang
RF
Manickam
Devika S
DS
Yin
Jing-Xiang
JX
Schultz
Harold D
HD
Bronich
Tatiana K
TK
Batrakova
Elena V
EV
Kabanov
Alexander V
AV
Zucker
Irving H
IH
Zimmerman
Matthew C
MC
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*
D004337:Drug Carriers; D000804:Angiotensin II; D013482:Superoxide Dismutase