Published Online
on June 24, 2004

A more recent version of this article appeared on August 1, 2004

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Submitted on January 30, 2004
Revised on April 7, 2004
Accepted on April 22, 2004

Overexpression of CuZn-SOD Prevents Lipopolysaccharide-Induced Endothelial Dysfunction

Sean P. Didion PhD; Dale A. Kinzenbaw BS; Pamela E. Fegan BS; Lisa A. Didion BS; and Frank M. Faraci PhD^*

From the Departments of Internal Medicine and Pharmacology, Cardiovascular Center, University of Iowa, Carver College of Medicine, Iowa City, Iowa.

^* To whom correspondence should be addressed. E-mail: frank-faraci{at}uiowa.edu.

Background and Purpose--Inflammation is thought to be a major contributor to carotid artery disease. Lipopolysaccharide (LPS) activates inflammatory mechanisms thought to contribute to endothelial dysfunction by mechanisms that are not well defined. The goal of this study was to determine whether overexpression of CuZn-SOD protects against LPS-induced increases in superoxide and endothelial dysfunction.

Methods--Carotid arteries from CuZn-SOD transgenic (SOD-Tg) and nontransgenic (non-Tg) littermates were examined in vitro. Superoxide levels were measured using lucigenin-enhanced chemiluminescence.

Results--In non-Tg mice, LPS (0.5 µg/mL for 22 hours) produced marked impairment of vasorelaxation in response to the endothelium-dependent dilator acetylcholine (ACh). For example, 100 µmol/L ACh relaxed carotid arteries from non-Tg mice by 86±6% and 38±8% after treatment with vehicle and LPS, respectively. In contrast, LPS did not significantly impair responses of carotid artery to ACh in SOD-Tg mice, and LPS had no effect on relaxation responses to the endothelium-independent dilator nitroprusside in carotid artery from non-Tg or SOD-Tg mice. LPS-induced increases in superoxide, as measured using lucigenin-enhanced chemiluminescence, were higher in vessels from non-Tg mice than from SOD-Tg mice.

Conclusions--These results indicate that LPS increases superoxide and impairs endothelium-dependent relaxation. Overexpression of the CuZn isoform of SOD effectively prevents LPS-induced oxidative stress and endothelial dysfunction in the carotid artery.

Key words: animal models • carotid arteries • endothelium • inflammation • reactive oxygen species • superoxide dismutase

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