This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 101/6/627    most recent CIRCRESAHA.107.158915v1 Alert me when this article is cited 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, D. Articles by Wilcox, C. S. Search for Related Content PubMed PubMed Citation Articles by Wang, D. Articles by Wilcox, C. S. Related Collections Endothelium/vascular type/nitric oxide Other Vascular biology

(Circulation Research. 2007;101:627.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Isoform-Specific Regulation by N^G,N^G-Dimethylarginine Dimethylaminohydrolase of Rat Serum Asymmetric Dimethylarginine and Vascular Endothelium-Derived Relaxing Factor/NO

Dan Wang^*, Pritmohinder S. Gill^*, Tinatin Chabrashvili^*, Maristela L. Onozato^*, Julie Raggio, Margarida Mendonca, Kathryn Dennehy, Min Li, Paul Modlinger, James Leiper, Patrick Vallance, Oscar Adler, Anna Leone, Akihiro Tojo, William J. Welch, Christopher S. Wilcox

From the Division of Nephrology and Hypertension and Cardiovascular Kidney Hypertension Institute (D.W., P.S.G., T.C., J.R., M.M., K.D., M.L., P.M., O.A., W.J.W., C.S.W.), Georgetown University, Washington, DC; Division of Nephrology and Endocrinology (M.L.O., A.T.), University of Tokyo, Japan; Department of Medicine (J.L., P.V.), University College, London, UK; Oxonon BioAnalysis (A.L.), Emeryville, Calif. Present address for P.V.: Glaxo Smith Kline, Greenford, Middlesex, UK.

Correspondence to Christopher S. Wilcox, MD, PhD, Division of Nephrology and Hypertension, Georgetown University Medical Center, 6 PHC, Suite F6003, 3800 Reservoir Rd NW, Washington, DC 20007. E-mail wilcoxch{at}georgetown.edu

Asymmetric dimethylarginine (ADMA), which inhibits NO synthase, is inactivated by N^G,N^G-dimethylarginine dimethylaminohydrolase (DDAH). We tested whether DDAH-1 or -2 regulates serum ADMA (S_ADMA) and/or endothelium-derived relaxing factor (EDRF)/NO. Small inhibitory (si)RNAs targeting DDAH-1 or -2, or an siRNA control were given intravenously to rats. After 72 hours, EDRF/NO was assessed from acetylcholine-induced, NO synthase–dependent relaxation and 4-amino-5-methylamino-2',7'-diflouroflourescein diacetate for NO activity in isolated mesenteric resistance vessels (MRVs). Expression of mRNA for DDAH-1 versus -2 was 2- and 7-fold higher in the kidney cortex and liver, respectively, whereas expression of DDAH-2 versus -1 was 5-fold higher in MRVs. The proteins and mRNAs for DDAH-1 or -2 were reduced selectively by 35% to 85% in the kidney cortex, liver, and MRVs 72 hours following the corresponding siRNA. S_ADMA was increased only after siDDAH-1 (266±25 versus 342±39 [mean±SD] nmol · L^–1; P<0.005), whereas EDRF/NO responses and NO activity were not changed consistently by siDDAH-1 but were greatly reduced after siDDAH-2. Mean arterial pressure was not changed significantly by any siRNA. In conclusion, S_ADMA is regulated by DDAH-1, which is expressed at sites of ADMA metabolism in the kidney cortex and liver, whereas EDRF/NO is regulated primarily by DDAH-2, which is expressed strongly in blood vessels. This implies specific functions of DDAH isoforms.

Key Words: RNA interference • hypertension • kidney • blood vessel • endothelium

This article has been cited by other articles:

				M. C. Richir, R. H. Bouwman, T. Teerlink, M. P.C. Siroen, T. P.G.M. de Vries, and P. A.M. van Leeuwen The Prominent Role of the Liver in the Elimination of Asymmetric Dimethylarginine (ADMA) and the Consequences of Impaired Hepatic Function JPEN J Parenter Enteral Nutr, November 1, 2008; 32(6): 613 - 621. [Abstract] [Full Text] [PDF]

				M. Sakurada, M. Shichiri, M. Imamura, H. Azuma, and Y. Hirata Nitric Oxide Upregulates Dimethylarginine Dimethylaminohydrolase-2 via Cyclic GMP Induction in Endothelial Cells Hypertension, November 1, 2008; 52(5): 903 - 909. [Abstract] [Full Text] [PDF]

				S. Dayal, R. N. Rodionov, E. Arning, T. Bottiglieri, M. Kimoto, D. J. Murry, J. P. Cooke, F. M. Faraci, and S. R. Lentz Tissue-specific downregulation of dimethylarginine dimethylaminohydrolase in hyperhomocysteinemia Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H816 - H825. [Abstract] [Full Text] [PDF]

				J. Jacobi, R. Maas, N. Cordasic, K. Koch, R. E. Schmieder, R. H. Boger, and K. F. Hilgers Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H1058 - H1066. [Abstract] [Full Text] [PDF]

				F. Palm, M. L. Onozato, Z. Luo, and C. S. Wilcox Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3227 - H3245. [Abstract] [Full Text] [PDF]