Chromosomal Localization, Gene Structure, and Expression Pattern of DDAH1: Comparison with DDAH2 and Implications for Evolutionary Origins

Tran, Cassandra; Fox, Margaret; Vallance, Patrick; Leiper, James

doi:10.1006/geno.2000.6262

Cited by 175 publications

(167 citation statements)

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“…DDAHII is expressed in highly vascularised tissues and in immune tissues whereas the distributions of DDAH1 correlates with those described for nNOS [41].…”

Section: Adma Metabolismsupporting

confidence: 60%

Cardiovascular Tests: Use & Limits of Biochemical Markers - Therapeutic Measurements of ADMA Involved in Cardiovascular Disorders

Smith¹,

Vallance²

2005

CPD

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“…DDAHII is expressed in highly vascularised tissues and in immune tissues whereas the distributions of DDAH1 correlates with those described for nNOS [41].…”

Section: Adma Metabolismsupporting

confidence: 60%

Cardiovascular Tests: Use & Limits of Biochemical Markers - Therapeutic Measurements of ADMA Involved in Cardiovascular Disorders

Smith¹,

Vallance²

2005

CPD

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“…Two isoforms of DDAH, DDAH1 and DDAH2, share similar gene structure and enzyme activity but display distinct tissue distributions. DDAH1 is found predominantly in tissues expressing neuronal NOS and in peripheral tissues such as liver, adrenal gland, testis, and kidney, whereas DDAH2 is found predominantly in tissues expressing endothelial NOS and inducible NOS, such as heart and aorta (34,35).…”

Section: Discussionmentioning

confidence: 99%

Farnesoid X Receptor Agonist Reduces Serum Asymmetric Dimethylarginine Levels through Hepatic Dimethylarginine Dimethylaminohydrolase-1 Gene Regulation

Chouinard

Cox

et al. 2006

Journal of Biological Chemistry

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The farnesoid X receptor (FXR, NR1H4) is a bile acid-responsive nuclear receptor that plays critical roles in the transcriptional regulation genes involved in cholesterol, bile acid, triglyceride, and carbohydrate metabolism. By microarray analysis of hepatic genes from female Zucker diabetic fatty (ZDF) rats treated with the FXR agonist GW4064, we have identified dimethylarginine dimethylaminohydrolase-1 (DDAH1) as an FXR target gene. DDAH1 is a key catabolic enzyme of asymmetric dimethylarginine (ADMA), a major endogenous nitric-oxide synthase inhibitor. Sequence analysis of the DDAH1 gene reveals the presence of an FXR response element (FXRE) located 90 kb downstream of the transcription initiation site and within the first intron. Functional analysis of the putative FXRE demonstrated GW4064 dose-dependent transcriptional activation from the element, and we have demonstrated that the FXRE sequence binds the FXR-RXR heterodimer. In vivo administration of GW4064 to female ZDF rats promoted a dose-dependent and >6-fold increase in hepatic DDAH1 gene expression. The level of serum ADMA was reduced concomitantly. These findings provide a mechanism by which FXR may increase endothelium-derived nitric oxide levels through modulation of serum ADMA levels via direct regulation of hepatic DDAH1 gene expression. Thus, beneficial clinical outcomes of FXR agonist therapy may include prevention of atherosclerosis and improvement of the metabolic syndrome.The global epidemic of obesity has led to an increasing prevalence of metabolic syndrome, a wide spectrum of metabolic risk factors characterized by abdominal obesity, low levels of high density lipoprotein cholesterol, high triglycerides, hypertension, glucose intolerance, and a systemic proinflammatory state. These risk factors are closely associated with incidence of cardiovascular disease, a leading cause of mortality in industrialized nations (1, 2). In the last decade, several ligand-activated nuclear receptors, such as peroxisome proliferator-activated receptors, liver X receptors, and thyroid hormone receptors, have emerged as promising targets for pharmacological intervention in the treatment of metabolic syndrome (3).Nuclear receptors are transcription factors that serve as intracellular sensors for endocrine hormones and lipid metabolites, such as bile acids, fatty acids, oxysterols, and xenobiotics. To control a variety of physiological processes, receptors bind to specific cis-acting DNA elements and regulate the expression of target genes by cofactor recruitment upon activation by ligands (4). Based on their pharmacological and ligand-binding properties, the nuclear receptor superfamily can be divided into three groups (5). The first group consists of classical steroid hormone receptors that are activated by high affinity ligands. The second group comprises low affinity receptors for metabolic intermediates. The third group corresponds to orphan receptors that have no known ligands.The farnesoid X receptor (FXR, 2 NR1H4) belongs to the second group of the nuc...

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“…DDAH metabolises 250 mol/L of the 300 mol/L generated daily, based upon urinary excretion of dimethylamine [108]. Two isoforms of DDAH have been identified [109]: human DDAHI was mapped to chromosome 1p22 and is more prevalent in the nervous system [110]. DDAHII was mapped to chromosome 6p21.3, close to the MHC region and dot-blot analyses revealed that DDAHII is located in vascularised and immune tissues [110].…”

Section: Formation and Metabolism Of Asymmetric Dimethylargininementioning

confidence: 99%

“…Two isoforms of DDAH have been identified [109]: human DDAHI was mapped to chromosome 1p22 and is more prevalent in the nervous system [110]. DDAHII was mapped to chromosome 6p21.3, close to the MHC region and dot-blot analyses revealed that DDAHII is located in vascularised and immune tissues [110]. Regulation of DDAHII is altered in development [110,111], perhaps reflecting a time when protein turnover and release of methylarginine is high.…”

Section: Formation and Metabolism Of Asymmetric Dimethylargininementioning

confidence: 99%

C-Reactive Protein and Asymmetric Dimethylarginine: Markers or Mediators in Cardiovascular Disorders?

Smith¹

2007

CPD

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This is an electronic version of an article published in Current Pharmaceutical Design, 13 (16). pp. [1619][1620][1621][1622][1623][1624][1625][1626][1627][1628][1629] 2007. The definitive version is available online at:http://www.bentham.org/cpd/index.htmThe WestminsterResearch online digital archive at the University of Westminster aims to make the research output of the University available to a wider audience. Copyright and Moral Rights remain with the authors and/or copyright owners. Users are permitted to download and/or print one copy for non-commercial private study or research. Further distribution and any use of material from within this archive for profit-making enterprises or for commercial gain is strictly forbidden.Whilst further distribution of specific materials from within this archive is forbidden, you may freely distribute the URL of WestminsterResearch.(http://www.wmin.ac.uk/westminsterresearch).In case of abuse or copyright appearing without permission e-mail wattsn@wmin.ac.uk. Abstract: C-reactive protein (CRP) has received much attention as a cardiovascular risk factor and has been recommended to be used in screening to assist in predicting the occurrence of cardiovascular disorders. There are numerous association studies documenting changes in circulating CRP concentrations, there are, however, fewer studies providing evidence that CRP mediates the progression of cardiovascular pathologies. Elucidating the potential mechanisms for CRP has been confounded by recent reports that contaminants of CRP are partially responsible for observed effects.In this review the use of CRP as a tool to predict cardiovascular disorders will be discussed alongside a more recently described cardiovascular risk factor asymmetric dimethylarginine (ADMA). An endogenously occurring nitric oxide synthase inhibitor, ADMA, is formed by the action of protein arginine methyltransferases and subsequent proteolysis and it is metabolised in vivo by the dimethylarginine dimethylaminohydrolases (DDAH). The evidence available documenting the effects of CRP and ADMA, the regulatory mechanisms and the genetic influences, will be discussed in order to determine whether CRP and ADMA are mediators in the progression of cardiovascular disorders or merely useful biomarkers.

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Chromosomal Localization, Gene Structure, and Expression Pattern of DDAH1: Comparison with DDAH2 and Implications for Evolutionary Origins

Cited by 175 publications

References 11 publications

Cardiovascular Tests: Use & Limits of Biochemical Markers - Therapeutic Measurements of ADMA Involved in Cardiovascular Disorders

Cardiovascular Tests: Use & Limits of Biochemical Markers - Therapeutic Measurements of ADMA Involved in Cardiovascular Disorders

Farnesoid X Receptor Agonist Reduces Serum Asymmetric Dimethylarginine Levels through Hepatic Dimethylarginine Dimethylaminohydrolase-1 Gene Regulation

C-Reactive Protein and Asymmetric Dimethylarginine: Markers or Mediators in Cardiovascular Disorders?

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