Published Online
on February 17, 2003

A more recent version of this article appeared on March 4, 2003

This Article Full Text (PDF) All Versions of this Article: 107/8/1195    most recent 01.CIR.0000051466.00227.13v1 Alert me when this article is cited Alert me if a correction is posted 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 Arrigoni, F. I. Articles by Leiper, J. M. Search for Related Content PubMed PubMed Citation Articles by Arrigoni, F. I. Articles by Leiper, J. M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB (L)-ARGININE Medline Plus Health Information Pulmonary Hypertension Related Collections Developmental biology Pulmonary biology and circulation Pulmonary circulation and disease Endothelium/vascular type/nitric oxide

Submitted on September 19, 2002
Revised on November 14, 2002
Accepted on November 15, 2002

Metabolism of Asymmetric Dimethylarginines Is Regulated in the Lung Developmentally and With Pulmonary Hypertension Induced by Hypobaric Hypoxia

Francesca I. Arrigoni PhD, Patrick Vallance FMedSci, FRCP, Sheila G. Haworth MD, PhD, and James M. Leiper PhD^*

From the Centre for Clinical Pharmacology (F.I.A., P.V., J.M.L.), The BHF Laboratories, The Rayne Institute, and the Developmental Vascular Biology and Pharmacology Unit (F.I.A., S.G.H.), The Institute of Child Health, London, UK.

^* To whom correspondence should be addressed. E-mail: james.leiper{at}ucl.ac.uk.

Background--Nitric oxide (NO) plays an important part in lowering pulmonary vascular resistance after birth, and in persistent pulmonary hypertension of the newborn (PPHN), NO-mediated dilation is dysfunctional. The endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) circulates in plasma, and its concentrations are elevated in certain cardiovascular diseases, including pulmonary hypertension. ADMA is metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), the activity of which regulates ADMA concentrations and provides a mechanism for modulating NO synthase in vivo. We investigated the changes in expression and activity of the 2 isoforms of DDAH in lungs from newborn piglets both during normal development and in PPHN.

Methods and Results--Using Western blotting, we showed that DDAHI expression did not change in the normal developing lung; however, DDAHII increased after birth and reached a peak at 1 day. This was reflected in an increase in total DDAH activity according to an L-citrulline assay. With pulmonary hypertension, no changes in DDAHI expression were observed, but DDAHII expression was markedly decreased compared with age-matched controls. Total DDAH activity was similarly reduced.

Conclusions--These results indicate that each DDAH isoform is differentially regulated during both lung development and PPHN. Suppression of DDAHII isoform expression may be a mechanism underlying PPHN.

Key words: nitric oxide • hypertension, pulmonary • asymmetric dimethylarginine

This article has been cited by other articles:

				X. Hu, X. Xu, G. Zhu, D. Atzler, M. Kimoto, J. Chen, E. Schwedhelm, N. Luneburg, R. H. Boger, P. Zhang, et al. Vascular Endothelial-Specific Dimethylarginine Dimethylaminohydrolase-1-Deficient Mice Reveal That Vascular Endothelium Plays an Important Role in Removing Asymmetric Dimethylarginine Circulation, December 1, 2009; 120(22): 2222 - 2229. [Abstract] [Full Text] [PDF]

				P. P. Landburg, T. Teerlink, E. J. van Beers, F. A.J. Muskiet, M. C. Kappers-Klunne, J. W.J. van Esser, M. R. Mac Gillavry, B. J. Biemond, D. P.M. Brandjes, A. J. Duits, et al. Association of asymmetric dimethylarginine with sickle cell disease-related pulmonary hypertension Haematologica, September 1, 2008; 93(9): 1410 - 1412. [Full Text] [PDF]

				B Wojciak-Stothard New drug targets for pulmonary hypertension: Rho GTPases in pulmonary vascular remodelling Postgrad. Med. J., July 1, 2008; 84(993): 348 - 353. [Abstract] [Full Text] [PDF]

				N. Sud, S. M. Wells, S. Sharma, D. A. Wiseman, J. Wilham, and S. M. Black Asymmetric dimethylarginine inhibits HSP90 activity in pulmonary arterial endothelial cells: role of mitochondrial dysfunction Am J Physiol Cell Physiol, June 1, 2008; 294(6): C1407 - C1418. [Abstract] [Full Text] [PDF]

				N. Skoro-Sajer, F. Mittermayer, A. Panzenboeck, D. Bonderman, R. Sadushi, R. Hitsch, J. Jakowitsch, W. Klepetko, M. P. Kneussl, M. Wolzt, et al. Asymmetric Dimethylarginine Is Increased in Chronic Thromboembolic Pulmonary Hypertension Am. J. Respir. Crit. Care Med., December 1, 2007; 176(11): 1154 - 1160. [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]

				A. Sasaki, S. Doi, S. Mizutani, and H. Azuma Roles of accumulated endogenous nitric oxide synthase inhibitors, enhanced arginase activity, and attenuated nitric oxide synthase activity in endothelial cells for pulmonary hypertension in rats Am J Physiol Lung Cell Mol Physiol, June 1, 2007; 292(6): L1480 - L1487. [Abstract] [Full Text] [PDF]

				E. Monsalve, P. J. Oviedo, M. A. Garcia-Perez, J. J. Tarin, A. Cano, and C. Hermenegildo Estradiol counteracts oxidized LDL-induced asymmetric dimethylarginine production by cultured human endothelial cells Cardiovasc Res, January 1, 2007; 73(1): 66 - 72. [Abstract] [Full Text] [PDF]

				A. O. Yildirim, P. Bulau, D. Zakrzewicz, K. E. Kitowska, N. Weissmann, F. Grimminger, R. E. Morty, and O. Eickelberg Increased Protein Arginine Methylation in Chronic Hypoxia: Role of Protein Arginine Methyltransferases Am. J. Respir. Cell Mol. Biol., October 1, 2006; 35(4): 436 - 443. [Abstract] [Full Text] [PDF]

				L.J. Ayling, G.St.J. Whitley, J.D. Aplin, and J.E. Cartwright Dimethylarginine dimethylaminohydrolase (DDAH) regulates trophoblast invasion and motility through effects on nitric oxide Hum. Reprod., October 1, 2006; 21(10): 2530 - 2537. [Abstract] [Full Text] [PDF]

				X. Wu, M. S. Chang, S. A. Mitsialis, and S. Kourembanas Hypoxia Regulates Bone Morphogenetic Protein Signaling Through C-Terminal-Binding Protein 1 Circ. Res., August 4, 2006; 99(3): 240 - 247. [Abstract] [Full Text] [PDF]

				R. K Oka, A. Szuba, J. C Giacomini, and J. P Cooke A pilot study of l-arginine supplementation on functional capacity in peripheral arterial disease Vascular Medicine, November 1, 2005; 10(4): 265 - 274. [Abstract] [PDF]

				Y. Chen, Y. Li, P. Zhang, J. H. Traverse, M. Hou, X. Xu, M. Kimoto, and R. J. Bache Dimethylarginine dimethylaminohydrolase and endothelial dysfunction in failing hearts Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2212 - H2219. [Abstract] [Full Text] [PDF]

				J. T. Kielstein, S. M. Bode-Boger, G. Hesse, J. Martens-Lobenhoffer, A. Takacs, D. Fliser, and M. M. Hoeper Asymmetrical Dimethylarginine in Idiopathic Pulmonary Arterial Hypertension Arterioscler Thromb Vasc Biol, July 1, 2005; 25(7): 1414 - 1418. [Abstract] [Full Text] [PDF]

				P. R. Reynolds, M. L. Mucenski, T. D. Le Cras, W. C. Nichols, and J. A. Whitsett Midkine Is Regulated by Hypoxia and Causes Pulmonary Vascular Remodeling J. Biol. Chem., August 27, 2004; 279(35): 37124 - 37132. [Abstract] [Full Text] [PDF]

				P. Vallance and J. Leiper Cardiovascular Biology of the Asymmetric Dimethylarginine:Dimethylarginine Dimethylaminohydrolase Pathway Arterioscler Thromb Vasc Biol, June 1, 2004; 24(6): 1023 - 1030. [Abstract] [Full Text] [PDF]

				J. P. Cooke Asymmetrical Dimethylarginine: The Uber Marker? Circulation, April 20, 2004; 109(15): 1813 - 1818. [Full Text] [PDF]

				J. P. Cooke A Novel Mechanism for Pulmonary Arterial Hypertension? Circulation, September 23, 2003; 108(12): 1420 - 1421. [Full Text] [PDF]

				L. J. Millatt, G. StJ. Whitley, D. Li, J. M. Leiper, H. M. Siragy, R. M. Carey, and R. A. Johns Evidence for Dysregulation of Dimethylarginine Dimethylaminohydrolase I in Chronic Hypoxia-Induced Pulmonary Hypertension Circulation, September 23, 2003; 108(12): 1493 - 1498. [Abstract] [Full Text] [PDF]