Effects of a common human gene variant of extracellular superoxide dismutase on endothelial function after endotoxin in mice

Donald D Lund; Yi Chu; Robert M Brooks; Frank M Faraci; Donald D Heistad

doi:10.1113/jphysiol.2007.140830

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Effects of a common human gene variant of extracellular superoxide dismutase on endothelial function after endotoxin in mice

Journal article

Open access

Peer reviewed

Effects of a common human gene variant of extracellular superoxide dismutase on endothelial function after endotoxin in mice

Donald D Lund, Yi Chu, Robert M Brooks, Frank M Faraci and Donald D Heistad

The Journal of physiology, Vol.584(Pt 2), pp.583-590

10/15/2007

DOI: 10.1113/jphysiol.2007.140830

PMCID: PMC2277153

PMID: 17717013

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Abstract

A common gene variant in the heparin-binding domain (HBD) of extracellular superoxide dismutase (ECSOD) may predispose human carriers to ischaemic heart disease. We have demonstrated that the HBD of ECSOD is important for ECSOD to restore vascular dysfunction produced by endotoxin. The purpose of this study was to determine whether the gene variant in the HBD of ECSOD (ECSOD(R213G)) protects against endothelial dysfunction in a model of inflammation. We constructed a recombinant adenovirus that expresses ECSOD(R213G). Adenoviral vectors expressing ECSOD, ECSOD(R213G) or beta-galactosidase (LacZ, a control) were injected i.v. in mice. After 3 days, at which time the plasma SOD activity is maximal, vehicle or endotoxin (lipopolysaccharide or LPS, 40 mg kg(-1)) was injected i.p. Vasomotor function of aorta in vitro was examined 1 day later. Maximal relaxation to sodium nitroprusside was similar in aorta from normal and LPS-treated mice. Maximal relaxation to acetylcholine (10(-5)) was impaired after LPS and LacZ (63 +/- 3%, mean +/- s.e.m.) compared to normal vessels (83 +/- 3%) (P < 0.05). Gene transfer of ECSOD improved (P < 0.05) relaxation in response to acetylcholine (76 +/- 5%) after LPS, whereas gene transfer of ECSOD(R213G) had no effect (65 +/- 4%). Superoxide was increased in aorta (measured using lucigenin and hydroethidine) after LPS, and levels of superoxide were significantly reduced following ECSOD but not ECSOD(R213G). Thus, ECSOD reduces superoxide and improves relaxation to acetylcholine in the aorta after LPS, while the ECSOD variant R213G had minimal effect. These findings suggest that, in contrast to ECSOD, the common human gene variant of ECSOD fails to protect against endothelial dysfunction produced by an inflammatory stimulus.

Superoxide Dismutase - genetics

Humans

beta-Galactosidase

Endothelium, Vascular - drug effects

Male

Nitroprusside - pharmacology

Endothelium, Vascular - enzymology

Lipopolysaccharides

Dose-Response Relationship, Drug

Superoxides - metabolism

Adenoviridae - genetics

Aorta - physiopathology

Dinoprost - pharmacology

Aorta - enzymology

Genes, Reporter

Superoxide Dismutase - metabolism

Disease Models, Animal

Vasoconstrictor Agents - pharmacology

Vasodilator Agents - pharmacology

Acetylcholine - pharmacology

Mice, Inbred C57BL

Endothelium, Vascular - physiopathology

Mice, Transgenic

Vasoconstriction - drug effects

Polymorphism, Genetic

Animals

Mice

Vasodilation - drug effects

Genetic Vectors

Inflammation - enzymology

Inflammation - physiopathology

Lac Operon

Details

Title: Subtitle: Effects of a common human gene variant of extracellular superoxide dismutase on endothelial function after endotoxin in mice
Creators: Donald D Lund - Department of Internal Medicine, Cardiovascular Center, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA
Yi Chu
Robert M Brooks
Frank M Faraci
Donald D Heistad
Resource Type: Journal article
Publication Details: The Journal of physiology, Vol.584(Pt 2), pp.583-590
DOI: 10.1113/jphysiol.2007.140830
PMID: 17717013
PMCID: PMC2277153
NLM abbreviation: J Physiol
ISSN: 0022-3751
eISSN: 1469-7793
Publisher: England
Grant note: DK 54759 / NIDDK NIH HHS R01 HL016066 / NHLBI NIH HHS R01 HL038901 / NHLBI NIH HHS P01 NS024621 / NINDS NIH HHS NS 24621 / NINDS NIH HHS HL 62984 / NHLBI NIH HHS HL 16066 / NHLBI NIH HHS P01 HL062984 / NHLBI NIH HHS HL 38901 / NHLBI NIH HHS P30 DK054759 / NIDDK NIH HHS
Language: English
Date published: 10/15/2007
Academic Unit: Cardiovascular Medicine; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040452802771

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