Pluronic-modified superoxide dismutase 1 attenuates angiotensin II-induced increase in intracellular superoxide in neurons

Xiang Yi, Matthew C. Zimmerman, Ruifang Yang, Jing Tong, Serguei Vinogradov, Alexander V. Kabanov

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Overexpressing superoxide dismutase 1 (SOD1; also called Cu/ZnSOD), an intracellular superoxide (O2.-)-scavenging enzyme, in central neurons inhibits angiotensin II (AngII) intraneuronal signaling and normalizes cardiovascular dysfunction in diseases associated with enhanced AngII signaling in the brain, including hypertension and heart failure. However, the blood-brain barrier and neuronal cell membranes impose a tremendous impediment for the delivery of SOD1 to central neurons, which hinders the potential therapeutic impact of SOD1 treatment on these diseases. To address this, we developed conjugates of SOD1 with poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) block copolymer (Pluronic) (SOD1-P85 and SOD1-L81), which retained significant SOD1 enzymatic activity. The modified SOD1 effectively scavenged xanthine oxidase/hypoxanthine-derived O2.-, as determined by HPLC and the measurement of 2-hydroxyethidium. Using catecholaminergic neurons, we observed an increase in neuronal uptake of SOD1-Pluronic after 1, 6, or 24h, compared to neurons treated with pure SOD1 or PEG-SOD1. Importantly, without inducing neuronal toxicity, SOD1-Pluronic conjugates significantly inhibited AngII-induced increases in intraneuronal O2.- levels. These data indicate that SOD1-Pluronic conjugates penetrate neuronal cell membranes, which results in elevated intracellular levels of functional SOD1. Pluronic conjugation may be a new delivery system for SOD1 into central neurons and therapeutically beneficial for AngII-related cardiovascular diseases.

Original languageEnglish (US)
Pages (from-to)548-558
Number of pages11
JournalFree Radical Biology and Medicine
Volume49
Issue number4
DOIs
StatePublished - Aug 2010

Keywords

  • 2-Hydroxyethidium
  • Angiotensin II
  • CATH.a neurons
  • Cellular delivery
  • Free radicals
  • Pluronic
  • Protein-polymer conjugation
  • Superoxide
  • Superoxide dismutase 1

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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