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

doi:10.1161/CIRCRESAHA.107.157727

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

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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, …

Circulation research, Vol.101(7), pp.692-702

09/28/2007

DOI: 10.1161/CIRCRESAHA.107.157727

PMID: 17704205

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Abstract

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 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.

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Title: Subtitle: Inducible NO Synthase–Dependent S -Nitrosylation and Activation of Arginase1 Contribute to Age-Related Endothelial Dysfunction
Creators: 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., 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
Hyun Kyo Lim - 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
Hyun Kyoung Lim - 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
Victor Miriel - 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
Tashalee Brown - 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
Meet Patel - 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
Sarit Balanson - 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
Sungwoo Ryoo - 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
Mirinda Anderson - 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
Kaikobad Irani - 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
Firdous Khanday - 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
Luigi Di Costanzo - 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
Daniel Nyhan - 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
Joshua M Hare - 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
David W Christianson - 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
Richard Rivers - 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
Artin Shoukas - 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
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
Resource Type: Journal article
Publication Details: Circulation research, Vol.101(7), pp.692-702
DOI: 10.1161/CIRCRESAHA.107.157727
PMID: 17704205
NLM abbreviation: Circ Res
ISSN: 0009-7330
eISSN: 1524-4571
Language: English
Date published: 09/28/2007
Academic Unit: Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984047784002771

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