Excessive production of
superoxide (O2(-)) in the central nervous system has been widely implicated in the pathogenesis of
cardiovascular diseases, including chronic
heart failure and
hypertension. In an attempt to overcome the failed therapeutic impact of currently available
antioxidants in
cardiovascular disease, we developed a nanomedicine-based delivery system for the O2(-)-scavenging
enzyme copper/
zinc superoxide dismutase (CuZnSOD), in which CuZnSOD
protein is electrostatically bound to a poly-
l-lysine (PLL50)-polyethylene glycol (PEG) block copolymer to form a CuZnSOD nanozyme. Various formulations of CuZnSOD nanozyme are covalently stabilized by either reducible or nonreducible crosslinked bonds between the PLL50-PEG
polymers. Herein, we tested the hypothesis that PLL50-PEG CuZnSOD nanozyme delivers active CuZnSOD
protein to neurons and decreases blood pressure in a mouse model of
angiotensin II (AngII)-dependent
hypertension. As determined by electron paramagnetic resonance spectroscopy, nanozymes retain full SOD enzymatic activity compared to native CuZnSOD
protein. Nonreducible CuZnSOD nanozyme delivers active CuZnSOD
protein to central neurons in culture (CATH.a neurons) without inducing significant neuronal toxicity. Furthermore, in vivo studies conducted in adult male C57BL/6 mice demonstrate that
hypertension established by chronic
subcutaneous infusion of AngII is significantly attenuated for up to 7 days after a single intracerebroventricular injection of nonreducible nanozyme. These data indicate the efficacy of nonreducible PLL50-PEG CuZnSOD nanozyme in counteracting excessive O2(-) and decreasing blood pressure in AngII-dependent hypertensive mice after central administration. Additionally, this study supports the further development of PLL50-PEG CuZnSOD nanozyme as an
antioxidant-based therapeutic option for
hypertension.