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Circulation Research. 2007
Published online before print August 2, 2007, doi: 10.1161/CIRCRESAHA.107.158915
A more recent version of this article appeared on September 14, 2007
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Submitted on January 23, 2007
Accepted on July 19, 2007

Isoform-Specific Regulation by NG-NG-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 ; and Christopher S. Wilcox *

From the Division of Nephrology and Hypertension and Cardiovascular Kidney 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.

* To whom correspondence should be addressed. E-mail: wilcoxch{at}georgetown.edu.

Asymmetric dimethylarginine (ADMA), which inhibits NO synthase, is inactivated by GN-GN-dimethylarginine dimethylaminohydrolase (DDAH). We tested whether DDAH-1 or -2 regulates serum ADMA (SADMA) and/or endothelium-derived relaxing factor (EDRF)/NO. Small inhibitory (si)RNAs targeting DDAH-1 or -2, or a siRNA control were given intravenously to rats. After 72 hours, EDRF/NO was assessed from acetylcholine-induced, NO synthase–dependent relaxation and 4,5-diaminofluorescein acetoxymethyl ester fluorescence for NO activity in isolated 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. SADMA 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 (assessed from 4,5-diaminofluorescein acetoxymethyl ester fluorescence) 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, SADMA 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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