Journal
CIRCULATION RESEARCH
Volume 101, Issue 7, Pages 692-702Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.107.157727
Keywords
arginase; NO synthase; S-nitrosylation; aging
Funding
- NHLBI NIH HHS [P01 HL65608, R01 HL70929] Funding Source: Medline
- NIA NIH HHS [R01 AG021523] Funding Source: Medline
- NIGMS NIH HHS [GM49758] Funding Source: Medline
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Endothelial function is impaired in aging because of a decrease in NO bioavailability. This may be, in part, attributable to increased arginase activity, which reciprocally regulates NO synthase ( NOS) by competing for the common substrate, L-arginine. However, the high K-m of arginase (> 1 mmol/ L) compared with NOS (2 to 20 mu mol/L) seemingly makes direct competition for substrate unlikely. One of the mechanisms by which NO exerts its effects is by posttranslational modification through S-nitrosylation of protein cysteines. We tested the hypothesis that arginase1 activity is modulated by this mechanism, which serves to alter its substrate affinity, allowing competition with NOS for L-arginine. We demonstrate that arginase1 activity is altered by S-nitrosylation, both in vitro and ex vivo. Furthermore, using site-directed mutagenesis we demonstrate that 2 cysteine residues (C168 and C303) are able to undergo nitrosylation. S-Nitrosylation of C303 stabilizes the arginase1 trimer and reduces its K-m value 6-fold. Finally, arginase1 nitrosylation is increased (and thus its Km decreased) in blood vessels from aging rats, likely contributing to impaired NO bioavailability and endothelial dysfunction. This is mediated by inducible NOS, which is expressed in the aging endothelium. These findings suggest that S-nitrosylated arginase1 can compete with NOS for L-arginine and contribute to endothelial dysfunction in the aging cardiovascular system.
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