Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 27, Pages 10485-10490Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0603918103
Keywords
arteriosclerosis; L-arginine; nitric oxide; endothelium; nitric-oxide synthase
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Funding
- NIA NIH HHS [R01 AG015857, AG-15857] Funding Source: Medline
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We evaluated the effects of a 0.5% cholesterol-enriched diet (HCD) on nitric-oxide synthase (NOS) and arginase expression and the modulating role of 17 beta-estradiol (E-2) on this phenomenon. Thirty oopherectomized rabbits were divided into three groups and treated for 15 weeks. Group I received normal chow; group II, HCD; and group III, HCD plus E-2 pellets. Animals in group II showed an increase in plasma lipids, and they demonstrated atheromatous lesions as well as expression of arginase I and II accompanied by a significant number of BrdU-positive cells in endothelial cells and intimal muscle cells, suggestive of an increase in cellular proliferation. There was significant expression of inducible NOS and increased staining of nitrotyrosine-positive areas. These were not observed in group I animals. In both groups, E-2 levels were low. In group III animals, E-2 supplementation led to a decrease in atheromatous lesions and BrdU-positive cells and reduced expression of both inducible NOS and arginase I and 11 accompanied by a decrease in nitrotyrosine staining. E2 levels were increased. Our results suggest that E-2 was responsible for these effects, despite the animals being hyperlipidemic, similar to those in group II. Because arginase is responsible for cell proliferation by converting L-arginine to polyamines, our results indicate that expression of arginase may play an important role in cellular proliferation in atherosclerosis, and inhibition of arginase expression by E-2 may be another potential mechanism in attenuating atherogenesis.
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