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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 107/4/1249    most recent 91393.2008v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kim, J. H. Articles by Berkowitz, D. E. PubMed PubMed Citation Articles by Kim, J. H. Articles by Berkowitz, D. E.

Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiffness in old rats

Department of ¹Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland; ; Department of ²Biomedical Engineering, Johns Hopkins Medical Institutions, Baltimore, Maryland; ; Department of ³Urology, Johns Hopkins Medical Institutions, Baltimore, Maryland; ; ⁴Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania; ; ⁵Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; ; ⁶Department of Anesthesiology and Pain Medicine, Yonsei University, Seoul, Korea; and ; ⁷Biology Program, Division of Life Sciences, Kangwon National University, Chuncheon, Korea

Submitted 17 October 2008 ; accepted in final form 28 July 2009

There is increasing evidence that upregulation of arginase contributes to impaired endothelial function in aging. In this study, we demonstrate that arginase upregulation leads to endothelial nitric oxide synthase (eNOS) uncoupling and that in vivo chronic inhibition of arginase restores nitroso-redox balance, improves endothelial function, and increases vascular compliance in old rats. Arginase activity in old rats was significantly increased compared with that shown in young rats. Old rats had significantly lower nitric oxide (NO) and higher superoxide (O) production than young. Acute inhibition of both NOS, with N^G-nitro-L-arginine methyl ester, and arginase, with 2(S)-amino- 6-boronohexanoic acid (ABH), significantly reduced O production in old rats but not in young. In addition, the ratio of eNOS dimer to monomer in old rats was significantly decreased compared with that shown in young rats. These results suggest that eNOS was uncoupled in old rats. Although the expression of arginase 1 and eNOS was similar in young and old rats, inducible NOS (iNOS) was significantly upregulated. Furthermore, S-nitrosylation of arginase 1 was significantly elevated in old rats. These findings support our previously published finding that iNOS nitrosylates and activates arginase 1 (Santhanam et al., Circ Res 101: 692–702, 2007). Chronic arginase inhibition in old rats preserved eNOS dimer-to-monomer ratio and significantly reduced O production and enhanced endothelial-dependent vasorelaxation to ACh. In addition, ABH significantly reduced vascular stiffness in old rats. These data indicate that iNOS-dependent S-nitrosylation of arginase 1 and the increase in arginase activity lead to eNOS uncoupling, contributing to the nitroso-redox imbalance, endothelial dysfunction, and vascular stiffness observed in vascular aging. We suggest that arginase is a viable target for therapy in age-dependent vascular stiffness.

aging; nitric oxide; S-nitrosylation; NOS uncoupling