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This Article Full Text Full Text (PDF) All Versions of this Article: 293/5/C1679    most recent 00224.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Pope, A. J. Articles by Cardounel, A. J. Search for Related Content PubMed PubMed Citation Articles by Pope, A. J. Articles by Cardounel, A. J.

VASCULAR BIOLOGY

Role of DDAH-1 in lipid peroxidation product-mediated inhibition of endothelial NO generation

Davis Heart and Lung Research Institute, Departments of ¹Pharmacology and ²Internal Medicine, The Ohio State University College of Medicine; and ³Columbus Children's Research Institute, Columbus, Ohio

Submitted 29 March 2007 ; accepted in final form 10 September 2007

Altered nitric oxide (NO) biosynthesis is thought to play a role in the initiation and progression of atherosclerosis and may contribute to increased risk seen in other cardiovascular diseases. It is hypothesized that altered NO bioavailability may result from an increase in endogenous NO synthase (NOS) inhibitors, asymmetric dimethly araginine (ADMA), and N^G-monomethyl arginine, which are normally metabolized by dimethyarginine dimethylamine hydrolase (DDAH). Lipid hydroperoxides and their degradation products are generated during inflammation and oxidative stress and have been implicated in the pathogenesis of cardiovascular disorders. Here, we show that the lipid hydroperoxide degradation product 4-hydroxy-2-nonenal (4-HNE) causes a dose-dependent decrease in NO generation from bovine aortic endothelial cells, accompanied by a decrease in DDAH enzyme activity. The inhibitory effects of 4-HNE (50 µM) on endothelial NO production were partially reversed with L-Arg supplementation (1 mM). Overexpression of human DDAH-1 along with antioxidant supplementation completely restored endothelial NO production following exposure to 4-HNE (50 µM). These results demonstrate a critical role for the endogenous methylarginines in the pathogenesis of endothelial dysfunction. Because lipid hydroperoxides and their degradation products are known to be involved in atherosclerosis, modulation of DDAH and methylarginines may serve as a novel therapeutic target in the treatment of cardiovascular disorders associated with oxidative stress.

nitric oxide; endothelial nitric oxide synthase; asymmetric dimethly araginine; 4-hydroxy-2-nonenal; dimethyarginine dimethylamine hydrolase

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