P3 - Redox Signaling in the Brain and Antioxidant-Based Therapeutics: Consequences for Hypertension

Abstract

Over the past two decades, hundreds of studies examining neuronal populations in unique cardiovascular control regions of the brain have revealed a role for reactive oxygen species (ROS) in mediating the elevated sympathetic output known to contribute to the pathogenesis of hypertension. We, and others, have been particularly interested in understanding the involvement of superoxide (O2--) in central neurons in mediating neuronal activation, sympathoexcitation, and hypertensive blood pressures. Numerous studies utilizing viral-mediated overexpression of copper/zinc superoxide dismutase (CuZnSOD) or manganese superoxide dismutase (MnSOD) in cardiovascular control brain regions have clearly identified O2-- as a primary ROS influencing sympathetic drive and systemic blood pressure. Recently, our group has focused on: 1) determining how O2-- mediates changes in neuronal excitability in hypertensive models; and 2) developing clinically relevant and novel antioxidant-based therapeutics to scavenge elevated O2-- levels in the brain for the improved treatment of hypertension. We have demonstrated that increased O2-- levels in neurons stimulated with angiotensin II (AngII), a pro-hypertensive peptide, inhibits outward potassium (K+) current, which contributes to enhanced neuronal firing. Additionally, we have identified redox-sensitive amino acids in neuronal calcium calmodulin kinase II-alpha (CaMKIIa) that mediate its inhibitory action on outward K+ current. In regards to developing novel antioxidant-based therapeutics, we have utilized nanotechnology approaches to create the so-called SOD nanozyme, which consists of CuZnSOD protein bound to poly-l-lysine (PLL50)-polyethylene glycol (PEG) block copolymer. We have shown that SOD nanozyme delivers active SOD protein to neurons and attenuates AngII-induced neuronal signaling. Most importantly, we have observed that central or peripheral (IV) administration of SOD nanozyme significantly decreases hypertensive blood pressures for up to 1 week following a single bolus injection. Collectively, these studies provide new insight into the precise intra-neuronal redox signaling mechanisms influencing blood pressure regulation, and identify novel antioxidant-based therapeutics for the improved treatment of hypertension.