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Vascular effects of a common gene variant of extracellular superoxide dismutase in heart failure

Cardiovascular Center and Departments of Internal Medicine and Pharmacology, University of Iowa Roy J. and Lucille A. Carver College of Medicine and Veterans Affairs Medical Center, Iowa City, Iowa

Submitted 19 January 2006 ; accepted in final form 23 March 2006

A common gene variant of human extracellular superoxide dismutase (ecSOD), in 5% of humans, is associated with increased risk of ischemic heart disease. The purpose of this study was to examine vascular effects of ecSOD with effects of the ecSOD variant (ecSOD_R213G) in rats with heart failure. Seven weeks after coronary artery ligation, we studied rats with heart failure and sham-operated rats. Adenoviral vectors expressing human ecSOD, ecSOD_R213G, or a control virus were injected intravenously. In the aorta from rats with heart failure, responses to acetylcholine (69 ± 4% relaxation, means ± SE) and basal levels of nitric oxide (NO) (vasoconstrictor responses to a NO synthase inhibitor) were greatly impaired, and levels of superoxide and peroxynitrite were increased. Gene transfer of ecSOD restored responses to acetylcholine (92 ± 2% relaxation) and basal levels of NO to normal and reduced levels of superoxide [from 2.3 ± 0.2 to 0.9 ± 0.2 relative light units per second per millimeter squared (RLU·s^–1·mm^–2)] and peroxynitrite (from 2.4 ± 0.2 to 0.9 ± 0.1 RLU·s^–1·mm^–2) in the aorta from rats with heart failure. Gene transfer of ecSOD_R213G produced little or no improvement. Responses to nitroprusside were not different among the groups. Expression of endogenous mRNA for SODs (CuZnSOD, MnSOD, and ecSOD) and endothelial NOS in the aorta was not different among the groups. In contrast to ecSOD, gene transfer of ecSOD_R213G in rats with heart failure has minimal beneficial effect on oxidative stress, endothelial function, or basal bioavailability of NO. We speculate that greatly diminished efficacy of ecSOD_R213G in protection against oxidative stress and endothelial dysfunction may contribute to increased risk of cardiovascular disease in humans with ecSOD_R213G.

gene therapy; endothelial function; oxidative stress

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