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(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

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