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

38 Citations (Scopus)

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 1 2010

Fingerprint

Poloxamer
Superoxides
Angiotensin II
Neurons
Superoxide Dismutase
Cell membranes
Cell Membrane
Xanthine Oxidase
Scavenging
Blood-Brain Barrier
Polyethylene glycols
Block copolymers
Toxicity
Brain
Cardiovascular Diseases
Heart Failure
High Pressure Liquid Chromatography
Superoxide Dismutase-1
Hypertension
Enzymes

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)

Cite this

Pluronic-modified superoxide dismutase 1 attenuates angiotensin II-induced increase in intracellular superoxide in neurons. / Yi, Xiang; Zimmerman, Matthew C; Yang, Ruifang; Tong, Jing; Vinogradov, Serguei; Kabanov, Alexander V.

In: Free Radical Biology and Medicine, Vol. 49, No. 4, 01.08.2010, p. 548-558.

Research output: Contribution to journalArticle

Yi, Xiang ; Zimmerman, Matthew C ; Yang, Ruifang ; Tong, Jing ; Vinogradov, Serguei ; Kabanov, Alexander V. / Pluronic-modified superoxide dismutase 1 attenuates angiotensin II-induced increase in intracellular superoxide in neurons. In: Free Radical Biology and Medicine. 2010 ; Vol. 49, No. 4. pp. 548-558.
@article{4e3469b98d1843bebf6aae3f1216f92a,
title = "Pluronic-modified superoxide dismutase 1 attenuates angiotensin II-induced increase in intracellular superoxide in neurons",
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.",
keywords = "2-Hydroxyethidium, Angiotensin II, CATH.a neurons, Cellular delivery, Free radicals, Pluronic, Protein-polymer conjugation, Superoxide, Superoxide dismutase 1",
author = "Xiang Yi and Zimmerman, {Matthew C} and Ruifang Yang and Jing Tong and Serguei Vinogradov and Kabanov, {Alexander V.}",
year = "2010",
month = "8",
day = "1",
doi = "10.1016/j.freeradbiomed.2010.04.039",
language = "English (US)",
volume = "49",
pages = "548--558",
journal = "Free Radical Biology and Medicine",
issn = "0891-5849",
publisher = "Elsevier Inc.",
number = "4",

}

TY - JOUR

T1 - Pluronic-modified superoxide dismutase 1 attenuates angiotensin II-induced increase in intracellular superoxide in neurons

AU - Yi, Xiang

AU - Zimmerman, Matthew C

AU - Yang, Ruifang

AU - Tong, Jing

AU - Vinogradov, Serguei

AU - Kabanov, Alexander V.

PY - 2010/8/1

Y1 - 2010/8/1

N2 - 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.

AB - 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.

KW - 2-Hydroxyethidium

KW - Angiotensin II

KW - CATH.a neurons

KW - Cellular delivery

KW - Free radicals

KW - Pluronic

KW - Protein-polymer conjugation

KW - Superoxide

KW - Superoxide dismutase 1

UR - http://www.scopus.com/inward/record.url?scp=77954539265&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954539265&partnerID=8YFLogxK

U2 - 10.1016/j.freeradbiomed.2010.04.039

DO - 10.1016/j.freeradbiomed.2010.04.039

M3 - Article

C2 - 20493251

AN - SCOPUS:77954539265

VL - 49

SP - 548

EP - 558

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

SN - 0891-5849

IS - 4

ER -