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(Circulation Research. 2007;101:692.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Inducible NO Synthase–Dependent S-Nitrosylation and Activation of Arginase1 Contribute to Age-Related Endothelial Dysfunction

Lakshmi Santhanam, Hyun Kyo Lim, Hyun Kyoung Lim, Victor Miriel, Tashalee Brown, Meet Patel, Sarit Balanson, Sungwoo Ryoo, Mirinda Anderson, Kaikobad Irani, Firdous Khanday, Luigi Di Costanzo, Daniel Nyhan, Joshua M. Hare, David W. Christianson, Richard Rivers, Artin Shoukas, Dan E. Berkowitz

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., 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; University of Miami Miller School of Medicine (J.M.H.), Fla; and Department of Chemistry (L.D.C., D.W.C.), University of Pennsylvania, Philadelphia.

Correspondence to Dan E. Berkowitz, Johns Hopkins University School of Medicine, 720 Rutland Ave, Traylor 621, Baltimore MD 21209. 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 common substrate, L-arginine. However, the high K_m 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 K_m value 6-fold. Finally, arginase1 nitrosylation is increased (and thus its K_m 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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