Nanoformulated superoxide dismutase 1 (SOD1): Implications for angiotensin II (AngII) and brain‐related cardiovascular diseases

Abstract

Due to possible toxicity and the inability of adenoviral vectors to target the brain, the therapeutic potential of adenoviral‐mediated gene transfer of SOD1 for the treatment of AngII‐dependent neuro‐cardiovascular diseases is limited. Thus, we developed a nanotechnology‐driven delivery system using a polyion complex micelle with a polyethylene glycol corona and a polyethyleneimine core that electrostatically binds SOD1 to form SOD1 nanozyme. We hypothesized that SOD1 nanozyme inhibits AngII intra‐neuronal signaling by delivering functional SOD1 to neurons. In catecholaminergic (CATH.a) neurons, SOD1 nanozyme, but not free SOD1 protein, inhibited the AngII‐induced increase in superoxide, as measured by DHE fluorescence and EPR spectroscopy. The AngII‐induced inhibition of K+ current (IKv) was also attenuated (P<0.05) in SOD1 nanozyme‐treated neurons (10 ± 1% IKv inhibition) compared to control and free SOD1‐treated neurons (38–40 ± 5% IKv inhibition). In conscious rabbits, the pressor response (21 ± 2 mmHg) induced by central‐injection of AngII (100 ng) was inhibited (6 ± 2 mmHg; P<0.05 vs. control) by intracarotid (i.c.) injection of SOD1 nanozyme (400 U/mL), but not free SOD1 protein (21 ± 2 mmHg). These data suggest that nanomedicine‐based delivery of SOD1 may provide a new therapeutic strategy for AngII‐dependent cardiovascular diseases associated with increased superoxide in the brain.