Role of DDAH-1 in lipid peroxidation product-mediated inhibition of endothelial NO generation.
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 microM) 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 microM). 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.
Pope
Arthur J
AJ
Davis Heart and Lung Research Institute, Department of Pharmacology, The Ohio State University College of Medicine, Ohio 43210, USA.
Druhan
Lawrence
L
Guzman
Jorge E
JE
Forbes
Scott P
SP
Murugesan
Velayutham
V
Lu
Deqin
D
Xia
Yong
Y
Chicoine
Louis G
LG
Parinandi
Narasimham L
NL
Cardounel
Arturo J
AJ
D000447:Aldehydes / Q000378:metabolism* / Q000494:pharmacology; D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000378:metabolism
D000447:Aldehydes; D000975:Antioxidants; D004791:Enzyme Inhibitors; D007476:Ionophores; D011994:Recombinant Proteins; D009569:Nitric Oxide; D000001:Calcimycin; C018524:N,N-dimethylarginine; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; D000581:Amidohydrolases; C059999:dimethylargininase; D005978:Glutathione; C027576:4-hydroxy-2-nonenal; D002118:Calcium