Published online before print August 17, 2007, doi: 10.1161/CIRCRESAHA.107.157727
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Submitted on September 25, 2006
Revised on July 25, 2007
Accepted on August 3, 2007
Inducible NO Synthase–Dependent S-Nitrosylation and Activation of Arginase1 Contribute to Age-Related Endothelial Dysfunction
Lakshmi Santhanam ;
From the Johns Hopkins University School of Medicine (L.S., H. Kyo Lim, H. Kyoung Lim, V.M., T.B., M.P., S.B., S.R., M.A., D.N., J.M.H., R.R., A.S., D.E.B.), Baltimore Md; Department of Anesthesiology and Pain Medicine (H. Kyo Lim), Yonsei University, Wonju, Korea; University of Pittsburgh Medical Center (K.I., F.K.), Pa; and Department of Chemistry (L.D.C., D.W.C.), University of Pennsylvania, Philadelphia.
* To whom correspondence should be addressed. E-mail: dberkowi{at}jhmi.edu.
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 same substrate, L-arginine. However, the high Km of arginase (>1 mmol/L) compared with NOS (2 to 20 µmol/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 Km 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.
Key words: arginase • NO synthase • S-nitrosylation • aging
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