Selective Substrate-Based Inhibitors of Mammalian Dimethylarginine Dimethylaminohydrolase

Rossiter, Sharon; Smith, Caroline L.; Malaki, Mohammed; Nandi, Manasi; Gill, Herpreet; Leiper, James; Vallance, Patrick; Selwood, David L.

doi:10.1021/jm050187a

Cited by 53 publications

(74 citation statements)

References 21 publications

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“…Three classes of DDAH inhibitors have been identified: pentafluorophenyl sulfonates (194); 2-chloroacetamidine (162); and a class of compounds derived the reversible inhibitor S-2-amino-4 (3-methylguanidino) butanoic acid (4124W) (141).…”

Section: Sites Of Ddah Expression and Functionmentioning

confidence: 99%

“…Moreover, 4124W dose dependently impairs the NO generation by all-trans-retinoic acid, inhibits IL-1␤-induced upregulation of DDAH activity in rat VSMCs, and abolishes the reduction in ADMA by IL-1␤ in these cells (3,191). Rossiter et al (141) proposed that changing the charge around the critical guanidine moiety could disrupt ADMA hydrolysis by DDAH. They tested this hypothesis using a series of analogs of 4124W with varying guanidine substituents and amino acid moieties some of which inhibited DDAH activity as selective, substrate-based inhibitors that were effective in vivo.…”

Section: Sites Of Ddah Expression and Functionmentioning

confidence: 99%

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Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems

Palm

Onozato²,

Luo³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

284

290

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Palm F, Onozato ML, Luo Z, Wilcox CS. Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems. Am J Physiol Heart Circ Physiol 293: H3227-H3245, 2007. First published October 12, 2007; doi:10.1152 doi:10. /ajpheart.00998.2007 )-dimethylarginine (ADMA) inhibits nitric oxide (NO) synthases (NOS). ADMA is a risk factor for endothelial dysfunction, cardiovascular mortality, and progression of chronic kidney disease. Two isoforms of dimethylarginine dimethylaminohydrolase (DDAH) metabolize ADMA. DDAH-1 is the predominant isoform in the proximal tubules of the kidney and in the liver. These organs extract ADMA from the circulation. DDAH-2 is the predominant isoform in the vasculature, where it is found in endothelial cells adjacent to the cell membrane and in intracellular vesicles and in vascular smooth muscle cells among the myofibrils and the nuclear envelope. In vivo gene silencing of DDAH-1 in the rat and DDAH ϩ/Ϫ mice both have increased circulating ADMA, whereas gene silencing of DDAH-2 reduces vascular NO generation and endothelium-derived relaxation factor responses. DDAH-2 also is expressed in the kidney in the macula densa and distal nephron. Angiotensin type 1 receptor activation in kidneys reduces the expression of DDAH-1 but increases the expression of DDAH-2. This rapidly evolving evidence of isoform-specific distribution and regulation of DDAH expression in the kidney and blood vessels provides potential mechanisms for nephron site-specific regulation of NO production. In this review, the recent advances in the regulation and function of DDAH enzymes, their roles in the regulation of NO generation, and their possible contribution to endothelial dysfunction in patients with cardiovascular and kidney diseases are discussed. nitric oxide synthase; hypertension; diabetes mellitus; chronic kidney disease; asymmetric dimethylarginineis an endogenous methylated amino acid that inhibits the constitutive endothelial (e) or type III and neuronal (n) or type I isoforms of nitric oxide (NO) synthase (NOS) (49,91,103,199). It is a less potent inhibitor of the inducible (i) or type II NOS isoform (41,191,213). Proteins are subject to methylation of arginine residues by protein arginine methyltransferase (PRMT). S-adenosylmethionine, which is synthesized from methionine and ATP, serves as the methyl donor and, in the process, is converted to S-adenosylhomocysteine, which itself can be hydrolyzed to homocysteine. Remethylation of homocysteine in the "remethylation pathway" regenerates methionine (14,179). ADMA is released by protein hydrolysis and exported from the cell and taken up by other cells via system y ϩ carriers of the cationic amino acid (CAT) family (14,196,212). ADMA is eliminated both by renal excretion and metabolic degradation. Its metabolism is facilitated by dimethylarginine dimethylaminohydrolases (DDAHs), which are expressed as type 1 and 2 isoforms. Recent studies have shown differential sites of expression of DDAH-1 and -2 in blo...

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Section: Sites Of Ddah Expression and Functionmentioning

confidence: 99%

Section: Sites Of Ddah Expression and Functionmentioning

confidence: 99%

Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems

Palm

Onozato²,

Luo³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

284

290

View full text Add to dashboard Cite

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“…29,38 The aim of this study was to use both genetic and pharmacological approaches to investigate whether a reduction in DDAH activity (and subsequent rise in ADMA) provides an alternative therapeutic mechanism to regulate NO overproduction and vascular hemodynamics in septic shock. The vascular effects of reduced DDAH activity were investigated in 2 commonly used rodent models of endotoxic shock, 12,[39][40][41] using a heterozygous DDAH1 knockout mouse (DDAH1 +/− ) and the novel DDAH inhibitor, N G -(2-methoxyethyl)-larginine (L-257), 39,42 which we now demonstrate for the first time is DDAH1 selective.…”

Section: Arterioscler Thromb Vasc Biolmentioning

confidence: 96%

Genetic and Pharmacological Inhibition of Dimethylarginine Dimethylaminohydrolase 1 Is Protective in Endotoxic Shock

Nandi¹,

Kelly²,

Torondel³

et al. 2012

ATVB

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Objective-The overproduction of vascular NO contributes toward the circulatory collapse observed in patients with septic shock. Dimethylarginine dimethylaminohydrolase (DDAH), which has 2 isoforms, metabolizes asymmetrically methylated arginines (asymmetric mono-or di-methylarginine), endogenously produced NO synthase inhibitors. We wished to investigate whether reducing DDAH1 activity, using genetic and pharmacological approaches, is protective during lipopolysaccharide-induced endotoxic shock. Methods and Results-Experiments were conducted in DDAH1 heterozygous knockout mice (DDAH1 +/− ) or naive rats treated with a synthetic pharmacological DDAH inhibitor (L-257). We demonstrate for the first time that L-257 is DDAH1 selective using recombinant human DDAH proteins. DDAH1 mRNA was expressed in aortic but not macrophage cDNA, and consistent with this expression profile, L-257 selectively inhibited NO production from lipopolysaccharide-treated aorta but not macrophages, in culture. Conscious and anesthetized cardiovascular hemodynamics were monitored using implanted radiotelemetry devices or invasive catheters, respectively. Lipopolysaccharide was administered intravenously to model endotoxemia, and all animals presented with circulatory shock. DDAH1 +/− mice or L-257-treated rats displayed attenuation in the rate of developed hypotension compared with wild-type littermates or vehicle control animals, respectively. Conclusion-Pharmacological

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“…Until recently the characterisation of DDAH had been limited by the availability of specific inhibitors. A panel of new inhibitors have been described which were based upon the original 4124W structure described by MacAllister [196] with IC50s approaching 20 mol/L and no effect on NOS activity [197]. As a therapeutic target these inhibitors also demonstrated that ADMA concentrations could be raised both in vitro and in vivo [197].…”

Section: Targets For Altering Adma Levelsmentioning

confidence: 99%

“…A panel of new inhibitors have been described which were based upon the original 4124W structure described by MacAllister [196] with IC50s approaching 20 mol/L and no effect on NOS activity [197]. As a therapeutic target these inhibitors also demonstrated that ADMA concentrations could be raised both in vitro and in vivo [197]. Other potential DDAH inhibitors include chloroacetamidine [198] and S-nitroso-L-homocysteine [199], however, these inhibi- tors have not yet been demonstrated to elicit a rise in ADMA concentrations in in vivo models.…”

Section: Targets For Altering Adma Levelsmentioning

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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Selective Substrate-Based Inhibitors of Mammalian Dimethylarginine Dimethylaminohydrolase

Cited by 53 publications

References 21 publications

Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems

Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems

Genetic and Pharmacological Inhibition of Dimethylarginine Dimethylaminohydrolase 1 Is Protective in Endotoxic Shock

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

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